{ "modules": [ { "id": "chromosome-segregation", "title": "Chromosome segregation: ParABS, PopZ, TipN", "summary": "After replication starts at the polar origin, the ParB-bound parS centromere beside the origin is moved to the opposite (new) pole by the ParA ATPase. TipN and PopZ keep transport directional, PopZ captures and anchors the arriving ori–ParB complex, and SMC loaded at parS aligns the chromosome arms.", "nodes": [ { "id": "ori", "label": "ori (Cori)", "kind": "dna-site", "description": "Replication origin; sits at one cell pole and, once replicated, one copy moves rapidly to the opposite pole.", "refs": [ "10.1073/pnas.96.19.10661", "10.1073/pnas.0807448105" ] }, { "id": "parS", "label": "parS", "kind": "dna-site", "description": "Centromere-like site near ori bound by ParB; the site of segregation force, independent of its chromosomal position.", "refs": [ "10.1073/pnas.0807448105", "10.1016/s0092-8674(00)81910-8" ] }, { "id": "ParB", "label": "ParB", "kind": "protein", "description": "Centromere-binding protein at parS; destabilizes ParA structures and is anchored at the poles by PopZ.", "refs": [ "10.1016/s0092-8674(00)81910-8", "10.1038/ncb2083", "10.1016/j.cell.2008.07.015" ] }, { "id": "ParA", "label": "ParA", "kind": "protein", "description": "ATPase forming a nucleoid-bound structure; ParB-stimulated disassembly moves the partition complex.", "refs": [ "10.1038/ncb2083", "10.1073/pnas.0807448105", "10.7554/elife.02758", "10.1073/pnas.1005274107" ] }, { "id": "PopZ", "label": "PopZ", "kind": "protein", "description": "Self-assembling proline-rich polar matrix; anchors ori–ParB at the poles and sequesters released ParA.", "refs": [ "10.1016/j.cell.2008.07.015", "10.1016/j.cell.2008.07.016", "10.1073/pnas.1405188111", "10.1083/jcb.201303036" ] }, { "id": "TipN", "label": "TipN", "kind": "protein", "description": "New-pole landmark; interacts with ParA at the new pole to keep partition-complex motion directional and fast.", "refs": [ "10.1016/j.cell.2005.12.040", "10.1038/emboj.2010.207", "10.1038/ncb2083" ] }, { "id": "SMC", "label": "SMC", "kind": "protein", "description": "Structural maintenance of chromosomes protein; loaded at parS in a ParB-dependent way, aligns the two chromosome arms.", "refs": [ "10.1073/pnas.96.19.10661", "10.1126/science.1242059", "10.1016/j.celrep.2017.08.026" ] }, { "id": "ZitP", "label": "ZitP", "kind": "protein", "description": "Bipolar zinc-finger protein that binds PopZ and regulates polar localization of ParB and PopZ and cytokinesis.", "refs": [ "10.7554/elife.20640" ] }, { "id": "MreB", "label": "MreB", "kind": "protein", "description": "Actin-like cytoskeleton; required for polar PopZ accumulation and for origin movement to the opposite pole.", "refs": [ "10.1016/j.cell.2008.07.015", "10.1016/j.cell.2006.05.038" ] }, { "id": "replication-initiation", "label": "Replication initiation", "kind": "process", "description": "Hand-off from the core cell-cycle module (DnaA/CtrA); duplicates the ori/parS region and starts segregation.", "refs": [ "10.1073/pnas.0807448105" ] }, { "id": "ori-translocation", "label": "Origin translocation", "kind": "process", "description": "Rapid, directed move of one ori/parS copy across the cell to the new pole; an ordered multistep process.", "refs": [ "10.1073/pnas.0807448105", "10.1073/pnas.1005274107", "10.1073/pnas.0402606101" ] }, { "id": "chromosome-layout", "label": "Ordered chromosome layout", "kind": "process", "description": "Each locus has a subcellular address in linear order along the cell; loci are placed as they are replicated.", "refs": [ "10.1073/pnas.0402606101", "10.1126/science.1242059" ] }, { "id": "MipZ", "label": "MipZ", "kind": "protein", "description": "Hand-off to division-site module: division inhibitor that binds ParB near ori and travels with it to the poles.", "refs": [ "10.1016/j.cell.2006.05.038" ] } ], "edges": [ { "source": "ParB", "target": "parS", "type": "binds", "note": "ParB binds DNA sequences adjacent to the origin (parS)", "refs": [ "10.1016/s0092-8674(00)81910-8", "10.1073/pnas.0807448105" ] }, { "source": "ori", "target": "ori-translocation", "type": "precedes", "note": "The 8-kb region holding ori and parS is what moves rapidly to the opposite pole", "refs": [ "10.1073/pnas.0807448105" ] }, { "source": "replication-initiation", "target": "ori-translocation", "type": "precedes", "note": "On initiation the ori/parS region moves to the far pole; segregation waits until parS is replicated", "refs": [ "10.1073/pnas.0807448105", "10.1073/pnas.96.19.10661" ] }, { "source": "ParB", "target": "ParA", "type": "inhibits", "note": "ParB binds and destabilizes ParA structures; ParA retracts on contact with ParB", "refs": [ "10.1038/ncb2083", "10.1073/pnas.1005274107" ] }, { "source": "ParA", "target": "ori-translocation", "type": "activates", "note": "ParA ATPase drives partition-complex transport; an ATPase mutant halts segregation", "refs": [ "10.1073/pnas.0807448105", "10.1038/ncb2083", "10.7554/elife.02758" ] }, { "source": "TipN", "target": "ParA", "type": "binds", "note": "TipN interacts with ParA at the new pole, keeping transport directional", "refs": [ "10.1038/emboj.2010.207", "10.1038/ncb2083" ] }, { "source": "PopZ", "target": "ParB", "type": "binds", "note": "PopZ binds ParB directly and tethers the ori–ParB complex at the pole", "refs": [ "10.1016/j.cell.2008.07.015", "10.1016/j.cell.2008.07.016" ] }, { "source": "PopZ", "target": "ParA", "type": "recruits", "note": "Released ParA is recruited into the polar PopZ structure, enforcing pole-directed transport", "refs": [ "10.1073/pnas.1405188111" ] }, { "source": "ParA", "target": "PopZ", "type": "activates", "note": "A local rise in ParA promotes PopZ matrix assembly at the new pole (unipolar to bipolar)", "refs": [ "10.1083/jcb.201303036" ] }, { "source": "MreB", "target": "PopZ", "type": "localizes", "note": "Polar PopZ accumulation by diffusion/capture requires the MreB cytoskeleton", "refs": [ "10.1016/j.cell.2008.07.015" ] }, { "source": "MreB", "target": "ori-translocation", "type": "activates", "note": "One replicated origin moves to the opposite end in an MreB-dependent manner", "refs": [ "10.1016/j.cell.2006.05.038" ] }, { "source": "ParB", "target": "SMC", "type": "recruits", "note": "SMC is recruited to parS and its arm-alignment activity depends on ParB", "refs": [ "10.1016/j.celrep.2017.08.026" ] }, { "source": "SMC", "target": "chromosome-layout", "type": "activates", "note": "SMC promotes colinearity of the chromosome arms; smc null cells mislocalize ori/ter", "refs": [ "10.1126/science.1242059", "10.1016/j.celrep.2017.08.026", "10.1073/pnas.96.19.10661" ] }, { "source": "ZitP", "target": "PopZ", "type": "localizes", "note": "ZitP binds PopZ and regulates the localization of PopZ and ParB", "refs": [ "10.7554/elife.20640" ] }, { "source": "ParB", "target": "MipZ", "type": "recruits", "note": "Hand-off: MipZ forms a complex with ParB near ori and moves with it to the poles", "refs": [ "10.1016/j.cell.2006.05.038" ] }, { "source": "ori-translocation", "target": "chromosome-layout", "type": "precedes", "note": "Newly replicated loci follow the origin in chronological order to their final positions", "refs": [ "10.1073/pnas.0402606101" ] } ], "steps": [ { "label": "Origin held at the pole", "text": "Before replication, the origin region with ParB-bound parS sits at one pole, held by the PopZ matrix.", "nodes": [ "ori", "parS", "ParB", "PopZ" ], "scene": { "cell": "swarmer", "features": [ "flagellum" ], "marks": [ { "kind": "nucleoid" }, { "kind": "origin", "at": [ "old-pole" ], "label": "ParB–parS", "note": "Origin-proximal parS centromere bound by ParB; sits at the flagellated (old) pole before replication" }, { "kind": "focus", "at": "old-pole", "label": "PopZ", "note": "Unipolar PopZ matrix tethering the origin–ParB complex" } ], "caption": "Swarmer cell: the single origin region with ParB-bound parS sits at the flagellated old pole, held by a unipolar PopZ matrix.", "refs": [ "10.1073/pnas.96.19.10661", "10.1016/j.cell.2008.07.015", "10.1016/j.cell.2008.07.016", "10.1083/jcb.201303036" ] } }, { "label": "Initiation releases the origin", "text": "Replication starts (core module hand-off); the duplicated ori/parS region is released and one copy begins to move.", "nodes": [ "replication-initiation", "ori", "parS" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "origin", "at": [ "old-pole", 0.2 ], "label": "ParB–parS", "note": "Replicated ori/parS region: one copy stays at the old pole, the other is released" }, { "kind": "focus", "at": "old-pole", "label": "PopZ" }, { "kind": "arrow", "from": 0.2, "to": 0.45, "label": "translocation", "note": "The ~8-kb ori/parS region starts moving toward the opposite pole" } ], "caption": "Stalked cell at replication initiation: the duplicated ori/parS region is released and one copy starts across the cell; the other stays at the old pole.", "refs": [ "10.1073/pnas.96.19.10661", "10.1073/pnas.0807448105", "10.1073/pnas.1005274107", "10.1016/j.cell.2008.07.015" ] } }, { "label": "ParA-driven transport", "text": "ParB on the moving centromere disassembles the nucleoid-bound ParA structure, pulling the complex across the cell.", "nodes": [ "ParB", "ParA", "ori-translocation", "MreB" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "origin", "at": [ "old-pole", 0.5 ], "label": "ParB–parS" }, { "kind": "gradient", "from": "new-pole", "label": "ParA", "note": "Nucleoid-bound ParA ahead of the moving complex, disassembled where ParB contacts it" }, { "kind": "arrow", "from": 0.5, "to": 0.8, "label": "translocation" }, { "kind": "focus", "at": "old-pole", "label": "PopZ" } ], "caption": "Mid-transport: the ParB–parS complex moves toward the new pole by disassembling the nucleoid-bound ParA structure ahead of it.", "refs": [ "10.1038/ncb2083", "10.1073/pnas.1005274107", "10.7554/elife.02758", "10.1073/pnas.1405188111", "10.1073/pnas.0807448105" ] } }, { "label": "Directionality", "text": "TipN at the new pole and PopZ sequestering released ParA keep transport heading to the new pole and prevent reversals.", "nodes": [ "TipN", "PopZ", "ParA" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "origin", "at": [ "old-pole", 0.7 ], "label": "ParB–parS" }, { "kind": "gradient", "from": "new-pole", "label": "ParA" }, { "kind": "focus", "at": "new-pole", "label": "TipN", "note": "New-pole landmark that interacts with ParA" }, { "kind": "focus", "at": "both-poles", "label": "PopZ", "note": "PopZ accumulates at the new pole during transport and sequesters released ParA" }, { "kind": "arrow", "from": 0.7, "to": "new-pole", "label": "translocation" } ], "caption": "TipN at the new pole and PopZ, now gathering at both poles, act on ParA so the ParB–parS complex keeps heading to the new pole.", "refs": [ "10.1038/emboj.2010.207", "10.1038/ncb2083", "10.1016/j.cell.2005.12.040", "10.1073/pnas.1405188111", "10.1083/jcb.201303036", "10.1016/j.cell.2008.07.015" ] } }, { "label": "Capture and anchoring", "text": "Bipolar PopZ captures the arriving ori–ParB complex; MipZ riding on ParB will position the division site.", "nodes": [ "PopZ", "ParB", "ZitP", "MipZ" ], "scene": { "cell": "early-predivisional", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "origin", "at": [ "old-pole", "new-pole" ], "label": "ParB–parS" }, { "kind": "focus", "at": "both-poles", "label": "PopZ", "note": "Bipolar PopZ anchors one origin–ParB complex at each pole" }, { "kind": "focus", "at": "both-poles", "label": "ZitP", "note": "Bipolar zinc-finger protein that binds PopZ" }, { "kind": "gradient", "from": "both-poles", "label": "MipZ", "note": "MipZ complexed with ParB travels with the origins to the poles" } ], "caption": "Segregation complete: bipolar PopZ (with ZitP) anchors an origin–ParB complex at each pole, and MipZ bound to ParB sits at both poles.", "refs": [ "10.1016/j.cell.2008.07.015", "10.1016/j.cell.2008.07.016", "10.1083/jcb.201303036", "10.7554/elife.20640", "10.1016/j.cell.2006.05.038", "10.1016/s0092-8674(00)81910-8" ] } }, { "label": "Arm alignment", "text": "SMC loaded at parS aligns the chromosome arms while loci reach ordered positions as they are replicated.", "nodes": [ "SMC", "parS", "chromosome-layout" ], "scene": { "cell": "predivisional", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid", "label": "SMC-aligned arms", "note": "SMC loaded at parS keeps the left and right arms side by side; loci lie in linear order along the cell" }, { "kind": "origin", "at": [ "old-pole", "new-pole" ], "label": "ParB–parS" } ], "caption": "Predivisional cell: origins at both poles, with each chromosome laid out along the cell and its two arms held alongside each other by SMC.", "refs": [ "10.1016/j.celrep.2017.08.026", "10.1126/science.1242059", "10.1073/pnas.0402606101", "10.1073/pnas.96.19.10661" ] } } ], "refs": [ "10.1016/j.cell.2005.12.040", "10.1016/j.cell.2006.05.038", "10.1016/j.cell.2008.07.015", "10.1016/j.cell.2008.07.016", "10.1016/j.celrep.2017.08.026", "10.1016/s0092-8674(00)81910-8", "10.1038/emboj.2010.207", "10.1038/ncb2083", "10.1073/pnas.0402606101", "10.1073/pnas.0807448105", "10.1073/pnas.1005274107", "10.1073/pnas.1405188111", "10.1073/pnas.96.19.10661", "10.1083/jcb.201303036", "10.1126/science.1242059", "10.7554/elife.02758", "10.7554/elife.20640" ] }, { "id": "division-site", "title": "Division-site selection and the divisome", "summary": "MipZ, carried to both poles by ParB, forms bipolar gradients that block FtsZ polymerization near the poles, so the Z-ring assembles at midcell where MipZ is lowest. FtsZ then recruits FzlA, FzlC and later divisome proteins (FtsA, FtsN, FtsW/FtsI, DipM) that constrict and separate the envelope.", "nodes": [ { "id": "ParB", "label": "ParB", "kind": "protein", "description": "Hand-off from chromosome-segregation module: centromere-binding protein at the polar ori regions; seeds MipZ dimers.", "refs": [ "10.1016/j.cell.2006.05.038", "10.1016/j.molcel.2012.03.004" ] }, { "id": "MipZ", "label": "MipZ", "kind": "protein", "description": "P-loop ATPase; ParB-stimulated ATP dimers bind the nucleoid near poles, forming gradients that block FtsZ polymerization.", "refs": [ "10.1016/j.cell.2006.05.038", "10.1016/j.molcel.2012.03.004", "10.1073/pnas.2208227119" ] }, { "id": "nucleoid", "label": "Nucleoid DNA", "kind": "structure", "description": "Chromosomal DNA that retains ATP-bound MipZ dimers near the poles until ATP hydrolysis releases monomers.", "refs": [ "10.1016/j.molcel.2012.03.004" ] }, { "id": "FtsZ", "label": "FtsZ", "kind": "protein", "description": "Tubulin-like GTPase; cell-cycle transcription and proteolysis limit it to replicating cells; also guides midcell PG precursor synthesis.", "refs": [ "10.1101/gad.12.6.880", "10.1111/j.1365-2958.2007.05720.x" ] }, { "id": "Z-ring", "label": "Z-ring", "kind": "structure", "description": "FtsZ ring assembled at midcell, the MipZ minimum; scaffolds the divisome and directs septal PG insertion.", "refs": [ "10.1016/j.cell.2006.05.038", "10.1111/j.1365-2958.2011.07677.x", "10.1111/mmi.13876" ] }, { "id": "FzlA", "label": "FzlA", "kind": "protein", "description": "Essential FtsZ-binding protein; curves FtsZ filaments into helical bundles resistant to MipZ; sets constriction rate.", "refs": [ "10.1016/j.molcel.2010.08.027", "10.1111/mmi.13876" ] }, { "id": "FzlC", "label": "FzlC", "kind": "protein", "description": "Early FtsZ-binding membrane anchor that tethers FtsZ via its C-terminal peptide; linked to cell wall hydrolysis.", "refs": [ "10.1016/j.molcel.2010.08.027", "10.1111/mmi.13388" ] }, { "id": "FtsA", "label": "FtsA", "kind": "protein", "description": "FtsZ membrane tether that in Caulobacter reaches midcell after a stable Z-ring and early PG-remodelling proteins.", "refs": [ "10.1111/j.1365-2958.2011.07677.x", "10.1111/mmi.13388" ] }, { "id": "FtsWI", "label": "FtsW / FtsI", "kind": "protein", "description": "Septal PG synthases; hyperactive alleles make fzlA non-essential, so FzlA signals their activation.", "refs": [ "10.1016/j.cub.2019.03.066" ] }, { "id": "FtsN", "label": "FtsN", "kind": "protein", "description": "Late cell-division protein that recruits DipM to the constriction site.", "refs": [ "10.1111/j.1365-2958.2010.07224.x" ] }, { "id": "DipM", "label": "DipM", "kind": "protein", "description": "LysM/LytM periplasmic PG-remodelling factor at the septum; needed for envelope invagination and outer-membrane constriction.", "refs": [ "10.1111/j.1365-2958.2010.07224.x", "10.1111/j.1365-2958.2010.07222.x", "10.1111/j.1365-2958.2010.07223.x" ] }, { "id": "constriction", "label": "Constriction & separation", "kind": "process", "description": "Coordinated invagination of inner membrane, PG and outer membrane, then cell separation.", "refs": [ "10.1111/j.1365-2958.2011.07677.x", "10.1111/j.1365-2958.2010.07224.x" ] }, { "id": "KidO", "label": "KidO", "kind": "protein", "description": "NAD(H)-binding oxidoreductase homolog acting on FtsZ and stimulating DivJ; ClpXP-degraded at G1→S together with CtrA.", "refs": [ "10.1016/j.devcel.2009.10.024" ] }, { "id": "CtrA", "label": "CtrA", "kind": "protein", "description": "Hand-off from core module: binds the ftsZ promoter and represses ftsZ transcription in swarmer cells.", "refs": [ "10.1101/gad.12.6.880" ] }, { "id": "crescentin", "label": "Crescentin (CreS)", "kind": "protein", "description": "Intermediate filament-like protein along the inner curvature; required for vibrioid shape (null cells are straight rods).", "refs": [ "10.1016/s0092-8674(03)00935-8", "10.1038/emboj.2009.61" ] }, { "id": "curvature", "label": "Cell curvature", "kind": "process", "description": "Crescent shape arising from an elongation-rate gradient across the sidewall imposed by the strained crescentin filament.", "refs": [ "10.1038/emboj.2009.61" ] } ], "edges": [ { "source": "ParB", "target": "MipZ", "type": "recruits", "note": "Polar ParB complexes bind MipZ and stimulate formation of ATP-bound MipZ dimers", "refs": [ "10.1016/j.cell.2006.05.038", "10.1016/j.molcel.2012.03.004" ] }, { "source": "MipZ", "target": "nucleoid", "type": "binds", "note": "ATP-MipZ dimers bind chromosomal DNA near poles; ATP hydrolysis releases diffusible monomers", "refs": [ "10.1016/j.molcel.2012.03.004" ] }, { "source": "MipZ", "target": "FtsZ", "type": "inhibits", "note": "MipZ blocks FtsZ polymerization: sequesters monomers and caps (+) ends of FtsZ polymers", "refs": [ "10.1016/j.cell.2006.05.038", "10.1073/pnas.2208227119" ] }, { "source": "FtsZ", "target": "Z-ring", "type": "precedes", "note": "FtsZ ring forms at midcell, the region of lowest MipZ concentration", "refs": [ "10.1016/j.cell.2006.05.038" ] }, { "source": "CtrA", "target": "FtsZ", "type": "represses-transcription", "note": "CtrA binds a site overlapping the ftsZ start site and represses it in swarmer cells", "refs": [ "10.1101/gad.12.6.880" ] }, { "source": "KidO", "target": "FtsZ", "type": "inhibits", "note": "KidO acts directly on FtsZ to tune cytokinesis with the cell cycle", "refs": [ "10.1016/j.devcel.2009.10.024" ] }, { "source": "FzlA", "target": "Z-ring", "type": "binds", "note": "FzlA binds and curves FtsZ filaments; FzlA–FtsZ structures resist MipZ depolymerization", "refs": [ "10.1016/j.molcel.2010.08.027", "10.1111/mmi.13876" ] }, { "source": "FzlC", "target": "Z-ring", "type": "binds", "note": "FzlC binds membranes and recruits FtsZ to them via the FtsZ C-terminal peptide", "refs": [ "10.1111/mmi.13388" ] }, { "source": "Z-ring", "target": "FtsA", "type": "precedes", "note": "FtsA arrives after Z-ring formation, early FtsZ-binders and PG-remodelling proteins", "refs": [ "10.1111/j.1365-2958.2011.07677.x", "10.1111/mmi.13388" ] }, { "source": "FzlA", "target": "FtsWI", "type": "activates", "note": "FzlA links FtsZ to activation and spatial orientation of the septal synthases FtsW/FtsI", "refs": [ "10.1016/j.cub.2019.03.066" ] }, { "source": "FtsN", "target": "DipM", "type": "recruits", "note": "DipM is recruited to the constriction site through interaction with FtsN", "refs": [ "10.1111/j.1365-2958.2010.07224.x" ] }, { "source": "Z-ring", "target": "DipM", "type": "recruits", "note": "DipM localizes to the division site FtsZ-dependently via its PG-binding LysM domains", "refs": [ "10.1111/j.1365-2958.2010.07222.x", "10.1111/j.1365-2958.2010.07223.x" ] }, { "source": "FtsWI", "target": "constriction", "type": "activates", "note": "Septal PG synthesis by FtsW/FtsI drives constriction; FzlA needed for proper rate", "refs": [ "10.1016/j.cub.2019.03.066" ] }, { "source": "DipM", "target": "constriction", "type": "activates", "note": "DipM remodels septal PG; without it outer-membrane invagination and separation are delayed", "refs": [ "10.1111/j.1365-2958.2010.07224.x", "10.1111/j.1365-2958.2010.07222.x" ] }, { "source": "crescentin", "target": "curvature", "type": "activates", "note": "Crescentin filament creates a sidewall elongation-rate gradient that curves the cell", "refs": [ "10.1016/s0092-8674(03)00935-8", "10.1038/emboj.2009.61" ] } ], "steps": [ { "label": "Bipolar MipZ gradients", "text": "After segregation, ParB at both poles builds ATP-MipZ dimers that bind the nucleoid, creating bipolar MipZ gradients.", "nodes": [ "ParB", "MipZ", "nucleoid" ], "scene": { "cell": "early-predivisional", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "origin", "at": [ "old-pole", "new-pole" ], "label": "ParB–parS" }, { "kind": "gradient", "from": "both-poles", "label": "MipZ", "note": "ParB stimulates ATP-MipZ dimers, retained on the nucleoid near the poles" } ], "caption": "After origin segregation, ParB at each pole seeds MipZ dimers on the nucleoid, so MipZ is high at both poles and lowest at midcell.", "refs": [ "10.1016/j.cell.2006.05.038", "10.1016/j.molcel.2012.03.004" ] } }, { "label": "FtsZ is licensed", "text": "CtrA repression of ftsZ lifts at G1→S as CtrA and KidO are degraded; MipZ keeps FtsZ off the poles so the Z-ring forms at midcell.", "nodes": [ "CtrA", "KidO", "FtsZ", "MipZ", "Z-ring" ], "scene": { "cell": "early-predivisional", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "gene", "label": "*ftsZ*", "state": "on", "note": "CtrA repression of the ftsZ promoter lifts as replication starts" }, { "kind": "gradient", "from": "both-poles", "label": "MipZ" }, { "kind": "ring", "label": "Z-ring", "note": "FtsZ polymerizes only where MipZ is lowest" } ], "caption": "ftsZ is transcribed once replication begins; with MipZ high at both poles, FtsZ assembles a Z-ring at midcell.", "refs": [ "10.1101/gad.12.6.880", "10.1016/j.cell.2006.05.038", "10.1073/pnas.2208227119", "10.1111/j.1365-2958.2007.05720.x" ] } }, { "label": "Early Z-ring partners", "text": "FzlA curves and stabilizes FtsZ filaments against MipZ, and FzlC anchors FtsZ to the membrane.", "nodes": [ "FzlA", "FzlC", "Z-ring" ], "scene": { "cell": "early-predivisional", "features": [ "stalk" ], "marks": [ { "kind": "gradient", "from": "both-poles", "label": "MipZ" }, { "kind": "ring", "label": "Z-ring" }, { "kind": "focus", "at": "midcell", "label": "FzlA", "note": "Binds and curves FtsZ filaments; FzlA–FtsZ structures resist MipZ" }, { "kind": "membrane", "at": "midcell", "label": "FzlC", "note": "Membrane anchor recruited to midcell via the FtsZ C-terminal peptide" } ], "caption": "Early partners join the midcell Z-ring: FzlA bundles FtsZ filaments against MipZ and FzlC tethers FtsZ to the membrane.", "refs": [ "10.1016/j.molcel.2010.08.027", "10.1111/mmi.13388", "10.1111/mmi.13876", "10.1111/j.1365-2958.2011.07677.x" ] } }, { "label": "Divisome maturation", "text": "PG-remodelling proteins arrive, then FtsA and core components; FtsN recruits the PG hydrolase factor DipM.", "nodes": [ "Z-ring", "FtsA", "FtsN", "DipM" ], "scene": { "cell": "predivisional", "features": [ "stalk" ], "marks": [ { "kind": "ring", "label": "Z-ring" }, { "kind": "membrane", "at": "midcell", "label": "FtsA", "note": "Arrives after the Z-ring and early PG-remodelling proteins" }, { "kind": "membrane", "at": "midcell", "label": "FtsN" }, { "kind": "membrane", "at": "midcell", "label": "DipM", "note": "Periplasmic; recruited via FtsN and its PG-binding LysM domains" } ], "caption": "The divisome matures at midcell: FtsA and core components join the Z-ring, and FtsN brings in the periplasmic PG-remodelling factor DipM.", "refs": [ "10.1111/j.1365-2958.2011.07677.x", "10.1111/mmi.13388", "10.1111/j.1365-2958.2010.07224.x", "10.1111/j.1365-2958.2010.07222.x", "10.1111/j.1365-2958.2010.07223.x" ] } }, { "label": "Constriction", "text": "FzlA signals FtsW/FtsI septal PG synthesis and DipM remodels PG so all envelope layers invaginate and the cells separate.", "nodes": [ "FzlA", "FtsWI", "DipM", "constriction" ], "scene": { "cell": "dividing", "features": [ "stalk" ], "marks": [ { "kind": "ring", "label": "Z-ring", "constricting": true }, { "kind": "focus", "at": "midcell", "label": "FzlA" }, { "kind": "membrane", "at": "midcell", "label": "FtsW/FtsI", "note": "Septal PG synthases; FzlA signals their activation" }, { "kind": "membrane", "at": "midcell", "label": "DipM" } ], "caption": "Constriction: septal PG synthesis by FtsW/FtsI, signalled by FzlA, and PG remodelling by DipM pull all envelope layers in at midcell.", "refs": [ "10.1016/j.cub.2019.03.066", "10.1111/mmi.13876", "10.1111/j.1365-2958.2010.07224.x", "10.1111/j.1365-2958.2010.07222.x", "10.1111/j.1365-2958.2011.07677.x" ] } }, { "label": "Cell shape", "text": "Independently, crescentin along the inner curvature biases sidewall growth to give the crescent shape.", "nodes": [ "crescentin", "curvature" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "filament", "label": "crescentin", "note": "Single filament beneath the membrane at the inner (concave) curvature" } ], "caption": "Crescentin forms a filament along the inner curvature beneath the membrane, slowing wall growth on that side to curve the cell.", "refs": [ "10.1016/s0092-8674(03)00935-8", "10.1038/emboj.2009.61" ] } } ], "refs": [ "10.1016/j.cell.2006.05.038", "10.1016/j.cub.2019.03.066", "10.1016/j.devcel.2009.10.024", "10.1016/j.molcel.2010.08.027", "10.1016/j.molcel.2012.03.004", "10.1016/s0092-8674(03)00935-8", "10.1038/emboj.2009.61", "10.1073/pnas.2208227119", "10.1101/gad.12.6.880", "10.1111/j.1365-2958.2007.05720.x", "10.1111/j.1365-2958.2010.07222.x", "10.1111/j.1365-2958.2010.07223.x", "10.1111/j.1365-2958.2010.07224.x", "10.1111/j.1365-2958.2011.07677.x", "10.1111/mmi.13388", "10.1111/mmi.13876" ] }, { "id": "flagellum-chemotaxis", "title": "Flagellar hierarchy, ejection and chemotaxis", "summary": "Flagellar genes form a four-tier hierarchy: CtrA activates class II genes (MS ring, switch, export, FlbD), whose assembled products license FlbD/σ54-dependent class III and IV transcription, and hook completion licenses flagellin translation (FlaF vs FlbT). The flagellum is built at the TipN/TipF-marked new pole, ejected in a PleD-dependent way at the swarmer-to-stalked transition, and a CtrA-dependent chemotaxis operon builds a polar receptor array.", "nodes": [ { "id": "CtrA", "label": "CtrA", "kind": "protein", "description": "Hand-off from core module: activates class II flagellar promoters and the major chemotaxis operon.", "refs": [ "10.1016/s0092-8674(00)80995-2", "10.1073/pnas.062065699", "10.1099/00221287-147-4-949" ] }, { "id": "TipN", "label": "TipN", "kind": "protein", "description": "Birth-scar landmark at the new pole; positions TipF so the flagellum is built at that pole.", "refs": [ "10.1016/j.cell.2006.01.019", "10.1016/j.cell.2005.12.040" ] }, { "id": "TipF", "label": "TipF", "kind": "protein", "description": "c-di-GMP receptor (degenerate EAL); flagellum assembly factor recruiting switch proteins and PflI to the new pole.", "refs": [ "10.1016/j.cell.2006.01.019", "10.1101/gad.222679.113" ] }, { "id": "classII", "label": "Class II genes", "kind": "gene-cluster", "description": "e.g. fliF, fliL, fliQ, fliP, flbD: MS ring, switch, flagellum-specific export apparatus and regulators.", "refs": [ "10.1007/bf00290715", "10.1128/jb.181.19.6160-6170.1999", "10.1128/jb.177.11.3241-3250.1995", "10.1128/jb.183.2.725-735.2001" ] }, { "id": "FlbD", "label": "FlbD", "kind": "protein", "description": "NtrC-like σ54 activator encoded by class II flbD; acts via ftr elements on class III and IV promoters.", "refs": [ "10.1073/pnas.87.6.2369", "10.1128/jb.177.11.3241-3250.1995" ] }, { "id": "FliX", "label": "FliX", "kind": "protein", "description": "Trans-acting factor that binds FlbD; represses FlbD when the class II structure is absent.", "refs": [ "10.1111/j.1365-2958.2004.04298.x" ] }, { "id": "RpoN", "label": "σ54 (RpoN)", "kind": "protein", "description": "σ54, placed at level II; required for class III transcription and for flagellum and stalk biogenesis.", "refs": [ "10.1007/bf00290715", "10.1101/gad.6.12a.2395" ] }, { "id": "classIII", "label": "Class III genes", "kind": "gene-cluster", "description": "e.g. flbG (hook operon), flgF, flgI, flgE: outer basal-body rings and hook; σ54/FlbD-dependent.", "refs": [ "10.1073/pnas.87.6.2369", "10.1128/jb.177.11.3241-3250.1995", "10.1128/jb.181.19.6160-6170.1999" ] }, { "id": "flagellins", "label": "Class IV flagellins", "kind": "gene-cluster", "description": "Six flagellins FljJ–FljO; transcribed by FlbD/σ54, translated only after the basal body–hook is complete.", "refs": [ "10.1128/jb.01172-10", "10.1128/jb.179.7.2281-2288.1997", "10.1111/j.1365-2958.2005.04745.x" ] }, { "id": "FlbT", "label": "FlbT", "kind": "protein", "description": "Negative regulator binding the fljK mRNA 5' UTR; blocks translation and promotes mRNA decay until the hook assembles.", "refs": [ "10.1128/jb.181.19.6160-6170.1999", "10.1046/j.1365-2958.2000.02108.x", "10.1111/j.1365-2958.2005.04745.x" ] }, { "id": "FlaF", "label": "FlaF", "kind": "protein", "description": "Cell-cycle-regulated protein required for fljK translation and filament assembly; opposes FlbT.", "refs": [ "10.1111/j.1365-2958.2005.04745.x" ] }, { "id": "flagellum", "label": "Polar flagellum", "kind": "structure", "description": "Single flagellum assembled at the swarmer pole of the predivisional cell; FliF MS ring anchors it in the membrane.", "refs": [ "10.1002/j.1460-2075.1996.tb00597.x", "10.1128/jb.01172-10" ] }, { "id": "PleD", "label": "PleD", "kind": "protein", "description": "Diguanylate cyclase response regulator; required for FliF degradation, flagellum ejection and efficient stalk formation.", "refs": [ "10.1046/j.1365-2958.1999.01358.x", "10.1128/jb.177.21.6223-6229.1995", "10.1101/gad.289504" ] }, { "id": "ejection", "label": "Flagellum ejection", "kind": "process", "description": "At the swarmer→stalked transition FliF is degraded and the flagellum released; a stalk then grows (stalk module).", "refs": [ "10.1002/j.1460-2075.1996.tb00597.x", "10.1046/j.1365-2958.1999.01358.x" ] }, { "id": "cheOperon", "label": "Major che operon", "kind": "gene-cluster", "description": "Major chemotaxis operon (mcpA…); CtrA-dependent, σ54- and class II-independent, peaks in predivisional cells.", "refs": [ "10.1099/00221287-147-4-949" ] }, { "id": "chemoArray", "label": "Chemoreceptor array", "kind": "structure", "description": "Polar McpA array, hexagonally packed near the motor; McpA is ClpX-dependently degraded at swarmer→stalked.", "refs": [ "10.1101/gad.6.5.825", "10.1111/j.1365-2958.2008.06219.x", "10.1128/jb.183.17.5001-5007.2001" ] } ], "edges": [ { "source": "CtrA", "target": "classII", "type": "activates-transcription", "note": "CtrA controls flagellar promoters; ChIP shows CtrA at the class II fliF promoter", "refs": [ "10.1016/s0092-8674(00)80995-2", "10.1073/pnas.062065699", "10.1111/j.1574-6968.2011.02275.x" ] }, { "source": "CtrA", "target": "cheOperon", "type": "activates-transcription", "note": "The major chemotaxis operon requires CtrA but not RpoN or class II genes", "refs": [ "10.1099/00221287-147-4-949" ] }, { "source": "TipN", "target": "TipF", "type": "localizes", "note": "TipF relies on TipN for positioning at the new pole", "refs": [ "10.1016/j.cell.2006.01.019" ] }, { "source": "TipF", "target": "classII", "type": "recruits", "note": "Activated TipF recruits flagellar switch proteins and PflI at the TipN-marked pole", "refs": [ "10.1101/gad.222679.113" ] }, { "source": "classII", "target": "classIII", "type": "precedes", "note": "Assembly of MS ring, switch and export apparatus is required for class III transcription", "refs": [ "10.1128/jb.181.19.6160-6170.1999", "10.1128/jb.179.7.2281-2288.1997" ] }, { "source": "FliX", "target": "FlbD", "type": "inhibits", "note": "FliX binds FlbD and represses it when the class II structure is missing", "refs": [ "10.1111/j.1365-2958.2004.04298.x" ] }, { "source": "FlbD", "target": "classIII", "type": "activates-transcription", "note": "FlbD activates σ54 promoters of class III genes via ftr enhancer elements", "refs": [ "10.1073/pnas.87.6.2369", "10.1128/jb.177.11.3241-3250.1995" ] }, { "source": "RpoN", "target": "classIII", "type": "activates-transcription", "note": "σ54 is required for level III transcription and recognizes the flbG promoter", "refs": [ "10.1007/bf00290715", "10.1101/gad.6.12a.2395" ] }, { "source": "FlbD", "target": "flagellins", "type": "activates-transcription", "note": "FlbD also activates σ54-dependent class IV promoters, incl. flagellin operons", "refs": [ "10.1073/pnas.87.6.2369", "10.1128/jb.177.11.3241-3250.1995" ] }, { "source": "classIII", "target": "flagellins", "type": "precedes", "note": "Basal body–hook completion is the checkpoint for flagellin translation", "refs": [ "10.1128/jb.179.7.2281-2288.1997", "10.1111/j.1365-2958.2005.04745.x" ] }, { "source": "FlbT", "target": "flagellins", "type": "represses", "note": "FlbT binds the fljK 5' UTR, inhibiting translation and destabilizing the mRNA", "refs": [ "10.1046/j.1365-2958.2000.02108.x", "10.1128/jb.181.19.6160-6170.1999" ] }, { "source": "FlaF", "target": "flagellins", "type": "activates", "note": "FlaF is required for fljK translation; FlbT and FlaF act in opposition", "refs": [ "10.1111/j.1365-2958.2005.04745.x" ] }, { "source": "classII", "target": "flagellum", "type": "precedes", "note": "FliF is inserted at the incipient swarmer pole where it initiates flagellar assembly", "refs": [ "10.1002/j.1460-2075.1996.tb00597.x" ] }, { "source": "flagellins", "target": "flagellum", "type": "precedes", "note": "The filament assembles from six flagellins; no single one is strictly required", "refs": [ "10.1128/jb.01172-10" ] }, { "source": "PleD", "target": "ejection", "type": "activates", "note": "pleD is required for efficient FliF removal and ejection of the flagellum", "refs": [ "10.1046/j.1365-2958.1999.01358.x" ] }, { "source": "flagellum", "target": "ejection", "type": "precedes", "note": "FliF is proteolysed at swarmer→stalked differentiation, coinciding with flagellum loss", "refs": [ "10.1002/j.1460-2075.1996.tb00597.x", "10.1046/j.1365-2958.1999.01358.x" ] }, { "source": "cheOperon", "target": "chemoArray", "type": "synthesizes", "note": "The che operon expresses mcpA; McpA localizes to the flagellated pole", "refs": [ "10.1099/00221287-147-4-949", "10.1101/gad.6.5.825" ] }, { "source": "chemoArray", "target": "flagellum", "type": "localizes", "note": "The receptor array lies tens of nm from the flagellar motor it controls", "refs": [ "10.1111/j.1365-2958.2008.06219.x" ] } ], "steps": [ { "label": "Mark the new pole", "text": "TipN marks the new pole; when c-di-GMP rises, TipF is activated there and recruits switch proteins (c-di-GMP module).", "nodes": [ "TipN", "TipF" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "level", "label": "c-di-GMP", "value": "high", "note": "c-di-GMP rises at the G1→S transition" }, { "kind": "focus", "at": "new-pole", "label": "TipN", "note": "Landmark at the pole born at the last division" }, { "kind": "focus", "at": "new-pole", "label": "TipF", "note": "c-di-GMP-activated TipF polarizes at the TipN pole and recruits switch proteins and PflI" } ], "caption": "Early S phase: as c-di-GMP rises, TipF is activated and joins the TipN landmark at the new pole, marking where the flagellum will be built.", "refs": [ "10.1016/j.cell.2005.12.040", "10.1016/j.cell.2006.01.019", "10.1101/gad.222679.113" ] } }, { "label": "Class II wave", "text": "CtrA activates class II genes (MS ring, switch, export apparatus, FlbD) and the major chemotaxis operon.", "nodes": [ "CtrA", "classII", "FlbD", "cheOperon" ], "scene": { "cell": "early-predivisional", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "cytoplasm", "labels": [ "CtrA" ], "where": "whole" }, { "kind": "gene", "label": "*fliF*", "state": "on", "note": "Class II flagellar promoter bound by CtrA" }, { "kind": "gene", "label": "*mcpA*", "state": "on", "note": "Major chemotaxis operon; CtrA-dependent, independent of σ54 and class II genes" } ], "caption": "CtrA switches on class II flagellar genes such as fliF and the major chemotaxis operon (mcpA), whose expression peaks in predivisional cells.", "refs": [ "10.1016/s0092-8674(00)80995-2", "10.1073/pnas.062065699", "10.1111/j.1574-6968.2011.02275.x", "10.1099/00221287-147-4-949" ] } }, { "label": "First checkpoint", "text": "Once the class II structure assembles, FliX no longer restrains FlbD; FlbD with σ54 activates class III basal-body and hook genes.", "nodes": [ "classII", "FliX", "FlbD", "RpoN", "classIII" ], "scene": { "cell": "predivisional", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "membrane", "at": "new-pole", "label": "FliF MS ring", "note": "Class II MS ring inserted at the incipient swarmer pole, initiating assembly" }, { "kind": "cytoplasm", "labels": [ "FlbD", "FliX", "σ54" ], "where": "whole" }, { "kind": "gene", "label": "*flbG*", "state": "on", "note": "Class III hook operon, σ54/FlbD-dependent" } ], "caption": "With the class II MS ring and switch built at the new pole, FliX stops restraining FlbD, and FlbD with σ54 turns on class III genes such as flbG.", "refs": [ "10.1002/j.1460-2075.1996.tb00597.x", "10.1128/jb.181.19.6160-6170.1999", "10.1111/j.1365-2958.2004.04298.x", "10.1073/pnas.87.6.2369", "10.1128/jb.177.11.3241-3250.1995", "10.1007/bf00290715" ] } }, { "label": "Second checkpoint", "text": "Flagellins are transcribed, but FlbT blocks their translation until the hook is complete; FlaF then promotes flagellin synthesis.", "nodes": [ "classIII", "flagellins", "FlbT", "FlaF" ], "scene": { "cell": "predivisional", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "membrane", "at": "new-pole", "label": "basal body–hook" }, { "kind": "gene", "label": "*fljK*", "state": "on", "note": "Flagellin mRNA is made, but translated only once the hook is complete" }, { "kind": "cytoplasm", "labels": [ "FlbT", "FlaF" ], "where": "whole" } ], "caption": "Flagellin genes are transcribed while the basal body and hook are built at the new pole; FlbT blocks flagellin translation, FlaF promotes it.", "refs": [ "10.1128/jb.179.7.2281-2288.1997", "10.1128/jb.181.19.6160-6170.1999", "10.1046/j.1365-2958.2000.02108.x", "10.1111/j.1365-2958.2005.04745.x", "10.1002/j.1460-2075.1996.tb00597.x" ] } }, { "label": "Swarmer equipment", "text": "The filament assembles at the new pole and the McpA chemoreceptor array forms close to the motor.", "nodes": [ "flagellins", "flagellum", "chemoArray" ], "scene": { "cell": "predivisional", "features": [ "stalk", "new-flagellum" ], "marks": [ { "kind": "membrane", "at": "new-pole", "label": "McpA array", "note": "Hexagonal chemoreceptor lattice tens of nm from the flagellar motor" } ], "caption": "The predivisional cell carries a single flagellum at the new pole, with the McpA chemoreceptor array beside its motor.", "refs": [ "10.1002/j.1460-2075.1996.tb00597.x", "10.1128/jb.01172-10", "10.1101/gad.6.5.825", "10.1111/j.1365-2958.2008.06219.x", "10.1099/00221287-147-4-949" ] } }, { "label": "Ejection", "text": "At the swarmer→stalked transition, PleD-dependent FliF degradation ejects the flagellum and McpA is proteolysed; a stalk grows there.", "nodes": [ "PleD", "ejection", "flagellum", "chemoArray" ], "scene": { "cell": "swarmer", "features": [ "ejecting-flagellum" ], "marks": [ { "kind": "level", "label": "c-di-GMP", "value": "high" }, { "kind": "focus", "at": "old-pole", "label": "PleD", "note": "Activated PleD is sequestered to the old (differentiating) pole" }, { "kind": "degraded", "at": "old-pole", "label": "FliF", "note": "MS-ring anchor turned over as the flagellum is released; needs PleD" }, { "kind": "degraded", "label": "McpA", "note": "ClpX-dependent proteolysis at the swarmer-to-stalked transition; drawn where the array sits" } ], "caption": "Swarmer-to-stalked transition: PleD gathers at the old pole, FliF is degraded and the flagellum released, and McpA is proteolysed.", "refs": [ "10.1002/j.1460-2075.1996.tb00597.x", "10.1046/j.1365-2958.1999.01358.x", "10.1101/gad.289504", "10.1111/mmi.12777", "10.1128/jb.183.17.5001-5007.2001", "10.1101/gad.6.5.825", "10.1101/gad.222679.113" ] } } ], "refs": [ "10.1002/j.1460-2075.1996.tb00597.x", "10.1007/bf00290715", "10.1016/j.cell.2005.12.040", "10.1016/j.cell.2006.01.019", "10.1016/s0092-8674(00)80995-2", "10.1046/j.1365-2958.1999.01358.x", "10.1046/j.1365-2958.2000.02108.x", "10.1073/pnas.062065699", "10.1073/pnas.87.6.2369", "10.1099/00221287-147-4-949", "10.1101/gad.222679.113", "10.1101/gad.289504", "10.1101/gad.6.12a.2395", "10.1101/gad.6.5.825", "10.1111/j.1365-2958.2004.04298.x", "10.1111/j.1365-2958.2005.04745.x", "10.1111/j.1365-2958.2008.06219.x", "10.1111/j.1574-6968.2011.02275.x", "10.1128/jb.01172-10", "10.1128/jb.177.11.3241-3250.1995", "10.1128/jb.177.21.6223-6229.1995", "10.1128/jb.179.7.2281-2288.1997", "10.1128/jb.181.19.6160-6170.1999", "10.1128/jb.183.17.5001-5007.2001", "10.1128/jb.183.2.725-735.2001" ] }, { "id": "pili-holdfast-adhesion", "title": "Pili, holdfast and surface adhesion", "summary": "Swarmer cells carry Tad (Cpa) pili and make the polysaccharide holdfast at the new pole. Pilin expression needs CtrA and PleC, and PodJ positions the pilus and holdfast machinery; surface contact sensed through pilus retraction and the flagellar motor triggers c-di-GMP-dependent holdfast synthesis via HfsJ, which HfiA inhibits.", "nodes": [ { "id": "CtrA", "label": "CtrA", "kind": "protein", "description": "Hand-off from core module: regulates the late-activated pilA promoter, timing pilus assembly.", "refs": [ "10.1093/emboj/19.13.3223" ] }, { "id": "PilA", "label": "PilA (pilA)", "kind": "protein", "description": "Major pilin subunit encoded in a seven-gene pilus cluster; PilA accumulation requires PleC activity.", "refs": [ "10.1093/emboj/19.13.3223", "10.1093/emboj/cdf454" ] }, { "id": "cpa", "label": "cpa genes", "kind": "gene-cluster", "description": "Pilus assembly genes incl. secretin CpaC and assembly factor CpaE, which localize to one pole before pili polymerize.", "refs": [ "10.1093/emboj/19.13.3223", "10.1093/emboj/cdf454" ] }, { "id": "PodJ", "label": "PodJ", "kind": "protein", "description": "Polar organelle development factor (two forms); localizes PleC, CpaE and the holdfast anchor to the new pole.", "refs": [ "10.1073/pnas.182411999", "10.1046/j.1365-2958.2003.03349.x", "10.1111/j.1365-2958.2010.07106.x" ] }, { "id": "PleC", "label": "PleC", "kind": "protein", "description": "Polar histidine kinase (core module link); controls PilA accumulation and asymmetric CpaE localization.", "refs": [ "10.1093/emboj/cdf454", "10.1073/pnas.182411999" ] }, { "id": "TadPilus", "label": "Tad pili", "kind": "structure", "description": "Polar swarmer pili with dynamic extension/retraction cycles; retraction pulls cells upright on surfaces.", "refs": [ "10.1093/emboj/19.13.3223", "10.1126/science.aan5706", "10.1128/mbio.01237-19" ] }, { "id": "surface", "label": "Surface contact", "kind": "process", "description": "Surface encounter, sensed as resistance to pilus retraction and as interference with the flagellar motor.", "refs": [ "10.1126/science.aan5706", "10.1126/science.aan5353" ] }, { "id": "DgcB", "label": "DgcB", "kind": "protein", "description": "Motor-associated diguanylate cyclase; makes c-di-GMP when surface contact interferes with the flagellar motor.", "refs": [ "10.1126/science.aan5353" ] }, { "id": "cdg", "label": "c-di-GMP", "kind": "small-molecule", "description": "Second messenger (c-di-GMP module); allosterically activates HfsJ and tunes pilus dynamics.", "refs": [ "10.1126/science.aan5353", "10.1128/mbio.01237-19" ] }, { "id": "PleD", "label": "PleD", "kind": "protein", "description": "Diguanylate cyclase; timing of holdfast formation in swarmer cells is post-translational and PleD-dependent.", "refs": [ "10.1128/jb.01725-05", "10.1111/mmi.14099" ] }, { "id": "HfiA", "label": "HfiA", "kind": "protein", "description": "68-residue holdfast inhibitor binding HfsJ; cell-cycle regulated, and a nutritional override limiting adhesion.", "refs": [ "10.1371/journal.pgen.1004101" ] }, { "id": "HfsJ", "label": "HfsJ", "kind": "protein", "description": "Glycolipid glycosyltransferase required for holdfast; inhibited by HfiA, allosterically activated by c-di-GMP.", "refs": [ "10.1371/journal.pgen.1004101", "10.1126/science.aan5353" ] }, { "id": "hfs", "label": "hfs genes", "kind": "gene-cluster", "description": "hfsDAB (export; Wza/GumC-like), hfsEFGH (repeat-unit synthesis, deacetylase) and hfsC polymerase.", "refs": [ "10.1128/jb.185.4.1432-1442.2003", "10.1128/jb.01003-08" ] }, { "id": "hfa", "label": "HfaA/B/D anchor", "kind": "gene-cluster", "description": "Outer-membrane anchor complex tethering the holdfast to the pole and later the stalk tip.", "refs": [ "10.1111/j.1365-2958.2010.07106.x" ] }, { "id": "holdfast", "label": "Holdfast", "kind": "structure", "description": "Polar GlcNAc-containing polysaccharide adhesin; single-cell detachment forces 0.11–2.26 µN.", "refs": [ "10.1128/jb.185.4.1432-1442.2003", "10.1073/pnas.0601705103" ] }, { "id": "flagellum", "label": "Flagellum", "kind": "structure", "description": "Hand-off from flagellum module: flagellum assembly feeds back to keep hfiA expressed (PleD-modulated).", "refs": [ "10.1111/mmi.14099", "10.1128/mbio.02273-18" ] } ], "edges": [ { "source": "CtrA", "target": "PilA", "type": "activates-transcription", "note": "pilA promoter is activated late in the cell cycle under CtrA control", "refs": [ "10.1093/emboj/19.13.3223" ] }, { "source": "PleC", "target": "PilA", "type": "activates", "note": "PleC activity controls accumulation of the PilA pilin subunit", "refs": [ "10.1093/emboj/cdf454", "10.1073/pnas.182411999" ] }, { "source": "PodJ", "target": "PleC", "type": "localizes", "note": "PodJ provides positional information for polar localization of PleC", "refs": [ "10.1073/pnas.182411999", "10.1046/j.1365-2958.2003.03349.x" ] }, { "source": "PodJ", "target": "cpa", "type": "localizes", "note": "PodJ is required for polar localization of the pilus assembly factor CpaE", "refs": [ "10.1073/pnas.182411999" ] }, { "source": "PleC", "target": "cpa", "type": "localizes", "note": "PleC activity drives the asymmetric distribution of CpaE to one pole", "refs": [ "10.1093/emboj/cdf454" ] }, { "source": "PilA", "target": "TadPilus", "type": "precedes", "note": "Timed pilin transcription controls when pili are assembled", "refs": [ "10.1093/emboj/19.13.3223" ] }, { "source": "cpa", "target": "TadPilus", "type": "synthesizes", "note": "Cluster encodes pilus assembly proteins; CpaC/CpaE are polar before filament polymerization", "refs": [ "10.1093/emboj/19.13.3223", "10.1093/emboj/cdf454" ] }, { "source": "TadPilus", "target": "holdfast", "type": "activates", "note": "Resistance to pilus retraction is sufficient to stimulate holdfast synthesis", "refs": [ "10.1126/science.aan5706", "10.1128/mbio.01237-19" ] }, { "source": "surface", "target": "DgcB", "type": "activates", "note": "Surface-induced motor interference stimulates c-di-GMP production by DgcB", "refs": [ "10.1126/science.aan5353" ] }, { "source": "DgcB", "target": "cdg", "type": "synthesizes", "note": "DgcB synthesizes c-di-GMP in the tactile response", "refs": [ "10.1126/science.aan5353" ] }, { "source": "cdg", "target": "HfsJ", "type": "activates", "note": "c-di-GMP allosterically activates HfsJ for rapid holdfast synthesis", "refs": [ "10.1126/science.aan5353" ] }, { "source": "cdg", "target": "TadPilus", "type": "activates", "note": "Intermediate c-di-GMP boosts pilus activity; peak levels drive pilus retraction", "refs": [ "10.1128/mbio.01237-19" ] }, { "source": "HfiA", "target": "HfsJ", "type": "inhibits", "note": "HfiA directly targets the glycosyltransferase HfsJ", "refs": [ "10.1371/journal.pgen.1004101" ] }, { "source": "HfsJ", "target": "holdfast", "type": "synthesizes", "note": "HfsJ is required for holdfast production", "refs": [ "10.1371/journal.pgen.1004101", "10.1126/science.aan5353" ] }, { "source": "hfs", "target": "holdfast", "type": "synthesizes", "note": "hfsDAB mutants make no holdfast; hfsG/hfsH are needed for synthesis", "refs": [ "10.1128/jb.185.4.1432-1442.2003", "10.1128/jb.01003-08" ] }, { "source": "hfa", "target": "holdfast", "type": "binds", "note": "HfaA/HfaB/HfaD form a complex anchoring the holdfast to the cell", "refs": [ "10.1111/j.1365-2958.2010.07106.x" ] }, { "source": "PodJ", "target": "hfa", "type": "localizes", "note": "Polar Hfa localization requires PodJ and holdfast secretion proteins", "refs": [ "10.1111/j.1365-2958.2010.07106.x" ] }, { "source": "PleD", "target": "holdfast", "type": "activates", "note": "Holdfast formation timing in swarmer cells depends on PleD", "refs": [ "10.1128/jb.01725-05" ] }, { "source": "flagellum", "target": "HfiA", "type": "activates-transcription", "note": "hfiA transcription falls in flagellar mutants (PleD-modulated), so they make holdfast early", "refs": [ "10.1111/mmi.14099", "10.1128/mbio.02273-18" ] } ], "steps": [ { "label": "Pole prepared", "text": "In the predivisional cell PodJ positions PleC, the pilus assembly factor CpaE and the HfaA/B/D anchor at the new pole.", "nodes": [ "PodJ", "PleC", "cpa", "hfa" ], "scene": { "cell": "predivisional", "features": [ "stalk", "new-flagellum" ], "marks": [ { "kind": "focus", "at": "new-pole", "label": "PodJ", "note": "Full-length PodJ localizes to the pole opposite the stalk (Hinz 2003; Viollier 2002 PNAS)." }, { "kind": "focus", "at": "new-pole", "label": "PleC", "note": "PodJ provides the positional cue for polar PleC (Viollier 2002 PNAS; Hinz 2003)." }, { "kind": "focus", "at": "new-pole", "label": "CpaE", "note": "Pilus assembly factor; asymmetric at one pole of the predivisional cell before pili form." }, { "kind": "membrane", "at": "new-pole", "label": "HfaA/B/D", "note": "Outer-membrane holdfast anchor at the late predivisional flagellar pole; needs PodJ (Hardy 2010)." } ], "caption": "Predivisional cell: PodJ, PleC, the pilus factor CpaE and the HfaA/B/D anchor gather at the new pole, opposite the stalk.", "refs": [ "10.1073/pnas.182411999", "10.1046/j.1365-2958.2003.03349.x", "10.1093/emboj/cdf454", "10.1111/j.1365-2958.2010.07106.x" ] } }, { "label": "Pili on the swarmer", "text": "CtrA-activated pilA and PleC-dependent PilA accumulation yield Tad pili on the newborn swarmer pole.", "nodes": [ "CtrA", "PilA", "PleC", "cpa", "TadPilus" ], "scene": { "cell": "swarmer", "features": [ "flagellum", "pili" ], "marks": [ { "kind": "focus", "at": "old-pole", "label": "PleC", "note": "PleC sits at the piliated pole before and during pilus assembly and controls PilA accumulation." }, { "kind": "focus", "at": "old-pole", "label": "CpaE", "note": "Kept at the single pole where pili are assembled; PleC activity makes this asymmetric." } ], "caption": "Newborn swarmer: Tad pili appear only at the flagellated pole, where PleC and the assembly factor CpaE sit.", "refs": [ "10.1093/emboj/19.13.3223", "10.1093/emboj/cdf454", "10.1073/pnas.182411999" ] } }, { "label": "Surface sensing", "text": "On contact, pilus retraction is resisted and the flagellar motor is obstructed; DgcB then makes c-di-GMP.", "nodes": [ "surface", "TadPilus", "DgcB", "cdg" ], "scene": { "cell": "swarmer", "features": [ "flagellum", "pili", "surface" ], "marks": [ { "kind": "focus", "at": "old-pole", "label": "DgcB", "note": "Motor-associated diguanylate cyclase (Hug 2017); at the flagellated swarmer pole (Abel 2011)." }, { "kind": "level", "label": "c-di-GMP", "value": "high", "note": "Surface-induced motor interference stimulates c-di-GMP production by DgcB." } ], "caption": "Swarmer touching a surface with its piliated, flagellated pole; resisted pilus retraction and a blocked motor lead DgcB to raise c-di-GMP.", "refs": [ "10.1126/science.aan5353", "10.1126/science.aan5706", "10.1128/mbio.01237-19", "10.1016/j.molcel.2011.07.018" ] } }, { "label": "Holdfast synthesis", "text": "c-di-GMP activates HfsJ and hfs enzymes build the polysaccharide; HfiA can veto it, and PleD times holdfast in development.", "nodes": [ "cdg", "HfsJ", "HfiA", "hfs", "PleD", "flagellum" ], "scene": { "cell": "swarmer", "features": [ "flagellum", "pili", "surface", "holdfast" ], "marks": [ { "kind": "level", "label": "c-di-GMP", "value": "high", "note": "c-di-GMP allosterically activates HfsJ for rapid holdfast synthesis (Hug 2017)." }, { "kind": "cytoplasm", "labels": [ "HfsJ", "HfiA" ], "where": "whole", "note": "Cellular location of HfsJ and HfiA is not established in the cited work; drawn unlocalized." } ], "caption": "Within seconds of contact the swarmer makes holdfast at the touching pole; c-di-GMP activates HfsJ, which HfiA can inhibit.", "refs": [ "10.1126/science.aan5353", "10.1126/science.aan5706", "10.1371/journal.pgen.1004101", "10.1128/jb.01725-05", "10.1111/j.1365-2958.2010.07106.x" ] } }, { "label": "Anchoring", "text": "HfaA/B/D tether the holdfast to the cell; single-cell adhesion reaches the micronewton range.", "nodes": [ "hfa", "holdfast" ], "scene": { "cell": "stalked", "features": [ "stalk", "holdfast", "surface" ], "marks": [ { "kind": "membrane", "at": "stalk-tip", "label": "HfaA/B/D", "note": "Outer-membrane anchor proteins localize at the stalk tip once the stalk is made at that pole (Hardy 2010)." } ], "caption": "Stalked cell glued to a surface by holdfast at the stalk tip, where the HfaA/B/D anchor tethers it; one cell can resist about 0.1–2 µN.", "refs": [ "10.1111/j.1365-2958.2010.07106.x", "10.1128/jb.185.4.1432-1442.2003", "10.1073/pnas.0601705103" ] } } ], "refs": [ "10.1046/j.1365-2958.2003.03349.x", "10.1073/pnas.0601705103", "10.1073/pnas.182411999", "10.1093/emboj/19.13.3223", "10.1093/emboj/cdf454", "10.1111/j.1365-2958.2010.07106.x", "10.1111/mmi.14099", "10.1126/science.aan5353", "10.1126/science.aan5706", "10.1128/jb.01003-08", "10.1128/jb.01725-05", "10.1128/jb.185.4.1432-1442.2003", "10.1128/mbio.01237-19", "10.1128/mbio.02273-18", "10.1371/journal.pgen.1004101" ] }, { "id": "c-di-GMP-signaling", "title": "c-di-GMP oscillation and its outputs", "summary": "c-di-GMP is low in G1 swarmer cells and rises at the G1→S transition, when the phosphodiesterase PdeA is degraded and the cyclases DgcB and PleD (activated by DivJ-dependent phosphorylation) act. The rising signal drives ShkA–TacA transcription, binds PopA and CckA to clear CtrA and allow replication, and activates TipF and HfsJ for polar morphogenesis.", "nodes": [ { "id": "DivJ", "label": "DivJ", "kind": "protein", "description": "Hand-off from core module: stalked-pole histidine kinase that positively controls PleD phosphorylation.", "refs": [ "10.1046/j.1365-2958.2003.03401.x" ] }, { "id": "PleC", "label": "PleC", "kind": "protein", "description": "Hand-off from core module: swarmer-pole histidine kinase that negatively modulates PleD phosphorylation.", "refs": [ "10.1046/j.1365-2958.2003.03401.x" ] }, { "id": "PleD", "label": "PleD", "kind": "protein", "description": "Response regulator with GGDEF output; phosphorylation-driven dimerization activates c-di-GMP synthesis and polar localization.", "refs": [ "10.1128/jb.177.21.6223-6229.1995", "10.1101/gad.289504", "10.1074/jbc.m704702200" ] }, { "id": "DgcB", "label": "DgcB", "kind": "protein", "description": "Diguanylate cyclase held in check by PdeA until G1→S; also a motor-associated surface sensor.", "refs": [ "10.1016/j.molcel.2011.07.018", "10.1126/science.aan5353" ] }, { "id": "PdeA", "label": "PdeA", "kind": "protein", "description": "GGDEF–EAL c-di-GMP phosphodiesterase (CC3396) activated by GTP; degraded by ClpXP via CpdR at G1→S.", "refs": [ "10.1074/jbc.m504429200", "10.1016/j.molcel.2011.07.018" ] }, { "id": "CpdR", "label": "CpdR", "kind": "protein", "description": "Hand-off from core module: response regulator that delivers PdeA to ClpXP in a phosphorylation-dependent way.", "refs": [ "10.1016/j.molcel.2011.07.018" ] }, { "id": "cdg", "label": "c-di-GMP", "kind": "small-molecule", "description": "Cyclic di-GMP; oscillates over the cycle (low in G1, upshift at G1→S) and is distributed asymmetrically at division.", "refs": [ "10.1371/journal.pgen.1003744", "10.1126/science.1188658", "10.1038/nature14473" ] }, { "id": "ShkA", "label": "ShkA", "kind": "protein", "description": "Hybrid histidine kinase stimulated by c-di-GMP binding its pseudo-receiver; relays via ShpA to TacA; later proteolysed.", "refs": [ "10.1038/s41467-020-14585-6", "10.1111/j.1365-2958.2005.04970.x" ] }, { "id": "TacA", "label": "TacA", "kind": "protein", "description": "σ54-dependent activator driving the G1/S-specific transcription program for morphogenesis and S-phase entry.", "refs": [ "10.1038/s41467-020-14585-6", "10.1111/j.1365-2958.2005.04970.x" ] }, { "id": "PopA", "label": "PopA", "kind": "protein", "description": "PleD paralogue turned c-di-GMP effector; c-di-GMP targets it to the old pole, where it links to RcdA.", "refs": [ "10.1101/gad.502409", "10.1111/mmi.12777" ] }, { "id": "CckA", "label": "CckA", "kind": "protein", "description": "Hand-off to core phosphorelay: essential kinase that c-di-GMP binding switches from kinase to phosphatase mode.", "refs": [ "10.1038/nature14473" ] }, { "id": "CtrA", "label": "CtrA", "kind": "protein", "description": "Hand-off to core module: replication inhibitor degraded by ClpXP at the old pole at G1→S.", "refs": [ "10.1101/gad.502409", "10.1016/j.molcel.2011.07.018" ] }, { "id": "TipF", "label": "TipF", "kind": "protein", "description": "Degenerate-EAL c-di-GMP receptor; activated, stabilized and polarized as c-di-GMP rises to nucleate the flagellum.", "refs": [ "10.1101/gad.222679.113" ] }, { "id": "DgrA", "label": "DgrA", "kind": "protein", "description": "PilZ-domain c-di-GMP receptor; high c-di-GMP or DgrA blocks motility by interfering with motor function.", "refs": [ "10.1073/pnas.0607738104" ] }, { "id": "HfsJ", "label": "HfsJ", "kind": "protein", "description": "Hand-off to pili-holdfast module: holdfast glycosyltransferase allosterically activated by c-di-GMP.", "refs": [ "10.1126/science.aan5353" ] }, { "id": "polarDev", "label": "Polar development", "kind": "process", "description": "Swarmer→stalked pole remodelling: flagellum ejection and stalk biogenesis.", "refs": [ "10.1046/j.1365-2958.1999.01358.x", "10.1046/j.1365-2958.2003.03401.x", "10.1111/j.1365-2958.2005.04970.x" ] } ], "edges": [ { "source": "DivJ", "target": "PleD", "type": "phosphorylates", "note": "DivJ positively controls the in vivo phosphorylation of PleD", "refs": [ "10.1046/j.1365-2958.2003.03401.x" ] }, { "source": "PleC", "target": "PleD", "type": "inhibits", "note": "PleC modulates PleD phosphorylation negatively", "refs": [ "10.1046/j.1365-2958.2003.03401.x" ] }, { "source": "PleD", "target": "cdg", "type": "synthesizes", "note": "Phosphorylated PleD dimerizes, localizes to the pole and synthesizes c-di-GMP", "refs": [ "10.1101/gad.289504", "10.1074/jbc.m704702200" ] }, { "source": "DgcB", "target": "cdg", "type": "synthesizes", "note": "Unopposed DgcB activity, with PleD, upshifts c-di-GMP at G1→S", "refs": [ "10.1016/j.molcel.2011.07.018" ] }, { "source": "PdeA", "target": "cdg", "type": "hydrolyzes", "note": "PdeA's EAL domain hydrolyses c-di-GMP to pGpG; it antagonizes DgcB until G1→S", "refs": [ "10.1074/jbc.m504429200", "10.1016/j.molcel.2011.07.018" ] }, { "source": "CpdR", "target": "PdeA", "type": "promotes-degradation", "note": "CpdR delivers PdeA to the ClpXP protease at the G1→S transition", "refs": [ "10.1016/j.molcel.2011.07.018" ] }, { "source": "cdg", "target": "ShkA", "type": "activates", "note": "c-di-GMP binds the ShkA pseudo-receiver domain and stimulates the kinase", "refs": [ "10.1038/s41467-020-14585-6" ] }, { "source": "ShkA", "target": "TacA", "type": "phosphotransfer", "note": "Phosphorelay ShkA→ShpA→TacA phosphorylates and activates TacA", "refs": [ "10.1111/j.1365-2958.2005.04970.x", "10.1038/s41467-020-14585-6" ] }, { "source": "TacA", "target": "polarDev", "type": "activates-transcription", "note": "TacA with σ54 activates stalk genes in a G1/S-specific program", "refs": [ "10.1111/j.1365-2958.2005.04970.x", "10.1038/s41467-020-14585-6" ] }, { "source": "cdg", "target": "PopA", "type": "binds", "note": "c-di-GMP binding to PopA's GGDEF domain targets PopA to the cell pole", "refs": [ "10.1101/gad.502409", "10.1111/mmi.12777" ] }, { "source": "PopA", "target": "CtrA", "type": "promotes-degradation", "note": "Polar PopA recruits CtrA via RcdA to the old pole for ClpXP proteolysis", "refs": [ "10.1101/gad.502409", "10.1111/mmi.12777" ] }, { "source": "cdg", "target": "CckA", "type": "inhibits", "note": "c-di-GMP binds CckA, inhibiting its kinase and stimulating its phosphatase activity", "refs": [ "10.1038/nature14473" ] }, { "source": "cdg", "target": "TipF", "type": "activates", "note": "Rising c-di-GMP activates, stabilizes and polarizes TipF", "refs": [ "10.1101/gad.222679.113" ] }, { "source": "cdg", "target": "DgrA", "type": "binds", "note": "DgrA is a PilZ-type c-di-GMP receptor controlling flagellar motor function", "refs": [ "10.1073/pnas.0607738104" ] }, { "source": "cdg", "target": "HfsJ", "type": "activates", "note": "c-di-GMP allosterically activates the holdfast glycosyltransferase HfsJ", "refs": [ "10.1126/science.aan5353" ] }, { "source": "PleD", "target": "polarDev", "type": "activates", "note": "PleD GGDEF signalling is needed for FliF degradation, flagellum ejection and stalk formation", "refs": [ "10.1046/j.1365-2958.1999.01358.x", "10.1046/j.1365-2958.2003.03401.x" ] } ], "steps": [ { "label": "G1: low c-di-GMP", "text": "In the swarmer, PleC keeps PleD phosphorylation low and PdeA hydrolyses c-di-GMP made by DgcB, so levels stay low.", "nodes": [ "PleC", "PleD", "PdeA", "DgcB", "cdg" ], "scene": { "cell": "swarmer", "features": [ "flagellum" ], "marks": [ { "kind": "focus", "at": "old-pole", "label": "PleC", "note": "Swarmer pole-specific kinase; negatively modulates PleD phosphorylation (Aldridge 2003)." }, { "kind": "focus", "at": "old-pole", "label": "PdeA", "note": "Venus-PdeA sits at the flagellated pole of the newborn swarmer (Abel 2011, results)." }, { "kind": "focus", "at": "old-pole", "label": "DgcB", "note": "DgcB persists at this pole in the newborn swarmer and interacts with PdeA (Abel 2011, results)." }, { "kind": "cytoplasm", "labels": [ "PleD" ], "where": "whole", "note": "Unphosphorylated PleD is not polar; it is sequestered to the pole only when activated (Paul 2004)." }, { "kind": "level", "label": "c-di-GMP", "value": "low", "note": "PdeA hydrolyses c-di-GMP and antagonizes DgcB until G1→S." } ], "caption": "G1 swarmer: PleC, the phosphodiesterase PdeA and the cyclase DgcB at the flagellated pole; PleD is diffuse and c-di-GMP stays low.", "refs": [ "10.1046/j.1365-2958.2003.03401.x", "10.1016/j.molcel.2011.07.018", "10.1074/jbc.m504429200", "10.1101/gad.289504", "10.1038/nature14473" ] } }, { "label": "G1→S upshift", "text": "CpdR delivers PdeA to ClpXP; unopposed DgcB plus DivJ-activated PleD raise c-di-GMP.", "nodes": [ "CpdR", "PdeA", "DgcB", "DivJ", "PleD", "cdg" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "focus", "at": "old-pole", "label": "DivJ", "note": "Localizes to the stalked pole during differentiation; promotes PleD phosphorylation (Aldridge 2003)." }, { "kind": "focus", "at": "old-pole", "label": "PleD", "note": "Phosphorylated, dimeric PleD is sequestered to the differentiating pole (Paul 2004, 2007; Ozaki 2014)." }, { "kind": "focus", "at": "old-pole", "label": "CpdR", "note": "Unphosphorylated CpdR at the old pole recruits ClpXP and delivers PdeA (Abel 2011)." }, { "kind": "degraded", "at": "old-pole", "label": "PdeA", "note": "PdeA moves transiently to the ClpXP-occupied stalked pole before being cleared (Abel 2011, results)." }, { "kind": "cytoplasm", "labels": [ "DgcB" ], "where": "whole", "note": "DgcB is released from the incipient stalked pole during differentiation (Abel 2011, results)." }, { "kind": "level", "label": "c-di-GMP", "value": "high", "note": "Unopposed DgcB plus activated PleD upshift c-di-GMP at G1→S." } ], "caption": "G1→S: at the new stalked pole DivJ activates PleD and CpdR brings PdeA to ClpXP for destruction, so c-di-GMP rises.", "refs": [ "10.1016/j.molcel.2011.07.018", "10.1046/j.1365-2958.2003.03401.x", "10.1101/gad.289504", "10.1074/jbc.m704702200", "10.1111/mmi.12777" ] } }, { "label": "G1/S transcription", "text": "Rising c-di-GMP stimulates ShkA, which activates TacA via ShpA to switch on the G1/S morphogenesis program.", "nodes": [ "cdg", "ShkA", "TacA", "polarDev" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "level", "label": "c-di-GMP", "value": "high", "note": "A gradual c-di-GMP increase stimulates ShkA via its pseudo-receiver domain." }, { "kind": "cytoplasm", "labels": [ "ShkA", "ShpA", "TacA" ], "where": "whole", "note": "Phosphorelay ShkA→ShpA→TacA; cellular location not established in the cited work." }, { "kind": "gene", "label": "*staR*", "state": "on", "note": "TacA–σ54 target gene that regulates stalk length (Biondi 2006)." } ], "caption": "G1/S: rising c-di-GMP drives the ShkA→ShpA→TacA relay, and TacA with σ54 switches on stalk genes such as staR.", "refs": [ "10.1038/s41467-020-14585-6", "10.1111/j.1365-2958.2005.04970.x" ] } }, { "label": "Replication licence", "text": "Peak c-di-GMP flips CckA to phosphatase mode and sends PopA to the old pole, where CtrA is degraded (core module).", "nodes": [ "cdg", "CckA", "PopA", "CtrA" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "focus", "at": "old-pole", "label": "PopA", "note": "c-di-GMP binding to its GGDEF domain targets PopA to the old pole." }, { "kind": "focus", "at": "old-pole", "label": "RcdA", "note": "PopA directs CtrA to the pole via a direct interaction with RcdA (Duerig 2009)." }, { "kind": "focus", "at": "old-pole", "label": "ClpXP", "note": "The protease localizes dynamically to the old pole at G1→S (Duerig 2009)." }, { "kind": "degraded", "at": "old-pole", "label": "CtrA", "note": "CtrA is sequestered to the old pole and rapidly degraded there, licensing replication." }, { "kind": "level", "label": "c-di-GMP", "value": "high", "note": "The c-di-GMP upshift also binds CckA and switches it from kinase to phosphatase (Lori 2015); not drawn." } ], "caption": "Entering S phase: c-di-GMP sends PopA to the old pole, where PopA and RcdA bring CtrA to ClpXP for degradation.", "refs": [ "10.1101/gad.502409", "10.1111/mmi.12777", "10.1016/j.molcel.2011.07.018", "10.1038/nature14473" ] } }, { "label": "Polar morphogenesis", "text": "c-di-GMP activates TipF for flagellum assembly and HfsJ for holdfast; DgrA links high c-di-GMP to motor control.", "nodes": [ "cdg", "TipF", "HfsJ", "DgrA", "PleD", "polarDev" ], "scene": { "cell": "early-predivisional", "features": [ "stalk", "holdfast" ], "marks": [ { "kind": "focus", "at": "new-pole", "label": "TipN", "note": "Landmark that marks the new pole through most of the cycle (Lam 2006)." }, { "kind": "focus", "at": "new-pole", "label": "TipF", "note": "c-di-GMP activates, stabilizes and polarizes TipF at the TipN pole to nucleate the flagellum (Davis 2013)." }, { "kind": "focus", "at": "old-pole", "label": "PleD", "note": "Active PleD at the old pole; its signalling is needed for flagellum ejection and stalk formation." }, { "kind": "level", "label": "c-di-GMP", "value": "high" } ], "caption": "Early S phase: high c-di-GMP polarizes TipF at the TipN-marked new pole to seed the next flagellum; PleD sits at the stalked pole.", "refs": [ "10.1101/gad.222679.113", "10.1016/j.cell.2005.12.040", "10.1101/gad.289504", "10.1111/mmi.12777", "10.1046/j.1365-2958.2003.03401.x", "10.1111/j.1365-2958.2010.07106.x" ] } }, { "label": "Reset at division", "text": "c-di-GMP drops at division, resetting TipF, and is split asymmetrically between daughters, imposing CckA replication asymmetry.", "nodes": [ "cdg", "TipF", "CckA" ], "scene": { "cell": "dividing", "features": [ "stalk", "new-flagellum" ], "marks": [ { "kind": "degraded", "at": "new-pole", "label": "TipF", "note": "TipF is removed at division as c-di-GMP drops, resetting flagellar polarity (Davis 2013)." } ], "caption": "At division c-di-GMP drops and TipF is cleared from the flagellated pole; the daughters inherit unequal c-di-GMP (not drawn).", "refs": [ "10.1101/gad.222679.113", "10.1126/science.1188658", "10.1038/nature14473", "10.1371/journal.pgen.1003744" ] } } ], "refs": [ "10.1016/j.molcel.2011.07.018", "10.1038/nature14473", "10.1038/s41467-020-14585-6", "10.1046/j.1365-2958.1999.01358.x", "10.1046/j.1365-2958.2003.03401.x", "10.1073/pnas.0607738104", "10.1074/jbc.m504429200", "10.1074/jbc.m704702200", "10.1101/gad.222679.113", "10.1101/gad.289504", "10.1101/gad.502409", "10.1111/j.1365-2958.2005.04970.x", "10.1111/mmi.12777", "10.1126/science.1188658", "10.1126/science.aan5353", "10.1128/jb.177.21.6223-6229.1995", "10.1371/journal.pgen.1003744" ] }, { "id": "stress-responses", "title": "Stress responses: GSR, SOS and starvation", "summary": "The general stress response is a partner switch: stress kinases pass phosphate through MrrA and PhyK to PhyR, whose σ-like domain then sequesters the anti-σ NepR and frees σT. DNA damage delays division via SOS-induced SidA and SOS-independent DidA, while starvation and proteotoxic stress arrest the cycle through (p)ppGpp and Lon-dependent loss of DnaA.", "nodes": [ { "id": "MrrA", "label": "MrrA", "kind": "protein", "description": "Single-domain response regulator phosphorylated by ≥6 stress kinases; hub feeding PhyK→PhyR and LovK.", "refs": [ "10.1128/mbio.00809-18" ] }, { "id": "PhyK", "label": "PhyK", "kind": "protein", "description": "Membrane histidine-kinase homolog (CC3474) essential for σT genes; acts as phosphotransferase from MrrA to PhyR.", "refs": [ "10.1111/j.1365-2958.2011.07668.x", "10.1128/mbio.00809-18" ] }, { "id": "PhyR", "label": "PhyR", "kind": "protein", "description": "Anti-anti-σ with σ-like and receiver domains; receiver phosphorylation opens the σ-like domain to bind NepR.", "refs": [ "10.1111/j.1365-2958.2010.07323.x", "10.1073/pnas.1116887109" ] }, { "id": "NepR", "label": "NepR", "kind": "protein", "description": "Anti-σ factor that binds σT; switches to binding phospho-PhyR under stress.", "refs": [ "10.1111/j.1365-2958.2011.07668.x", "10.1073/pnas.1116887109" ] }, { "id": "sigT", "label": "σT (EcfG)", "kind": "protein", "description": "ECF σ factor σT, master regulator of the general stress response; needed to survive osmotic and oxidative stress.", "refs": [ "10.1111/j.1365-2958.2007.06005.x", "10.1111/j.1365-2958.2011.07668.x" ] }, { "id": "GSR", "label": "σT regulon", "kind": "gene-cluster", "description": "General stress regulon (~40 genes incl. sigU, sigR, envelope and stress genes), shared with PhyK/PhyR control.", "refs": [ "10.1111/j.1365-2958.2007.06005.x", "10.1111/j.1365-2958.2011.07668.x" ] }, { "id": "LovKR", "label": "LovK–LovR", "kind": "protein", "description": "LOV kinase LovK and receiver LovR; repress the GSR by acting as a phosphate sink; also modulate cell attachment.", "refs": [ "10.1128/jb.00182-12", "10.1128/mbio.00809-18", "10.1073/pnas.0705887104" ] }, { "id": "CtrA", "label": "CtrA", "kind": "protein", "description": "Hand-off to core module: inhibited after DNA damage; degraded in carbon starvation in a SigT-dependent way.", "refs": [ "10.1101/gad.2038911", "10.1371/journal.pone.0018179" ] }, { "id": "DNAdamage", "label": "DNA damage", "kind": "process", "description": "DNA damage triggers the LexA-controlled SOS regulon and SOS-independent responses that delay division.", "refs": [ "10.1101/gad.2038911", "10.1371/journal.pbio.1001977" ] }, { "id": "LexA", "label": "LexA", "kind": "protein", "description": "SOS repressor of ≥37 genes binding the GTTCN7GTTC operator; its cleavage after damage induces SOS genes.", "refs": [ "10.1128/jb.01419-07", "10.1371/journal.pbio.1001977" ] }, { "id": "SidA", "label": "SidA", "kind": "protein", "description": "29-aa SOS-induced membrane protein; binds FtsW to block final constriction after DNA damage.", "refs": [ "10.1101/gad.2038911" ] }, { "id": "DidA", "label": "DidA", "kind": "protein", "description": "SOS-independent division inhibitor induced by DNA damage via the transcription factor DriD; binds FtsN.", "refs": [ "10.1371/journal.pbio.1001977" ] }, { "id": "FtsWN", "label": "FtsW / FtsN", "kind": "protein", "description": "Late divisome proteins driving septal wall synthesis (division-site module); targets of SidA and DidA.", "refs": [ "10.1101/gad.2038911", "10.1371/journal.pbio.1001977" ] }, { "id": "SpoT", "label": "SpoT", "kind": "protein", "description": "Sole RelA/SpoT homolog; ribosome-bound, makes (p)ppGpp on carbon or nitrogen (glutamine, via PTS-Ntr) starvation.", "refs": [ "10.1111/j.1365-2958.2011.07602.x", "10.1128/jb.00700-08", "10.1038/ncomms11423" ] }, { "id": "ppGpp", "label": "(p)ppGpp", "kind": "small-molecule", "description": "Alarmone; with polyphosphate keeps starved swarmer cells in G1 and extends the G1 phase.", "refs": [ "10.1128/jb.05932-11", "10.1038/ncomms11423", "10.1128/jb.00700-08" ] }, { "id": "DnaA", "label": "DnaA", "kind": "protein", "description": "Hand-off to core module: unstable replication initiator; cleared on starvation (less translation, Lon) and proteotoxic stress.", "refs": [ "10.1111/j.1365-2958.2004.04459.x", "10.1371/journal.pgen.1005342", "10.1016/j.cell.2013.06.034" ] }, { "id": "Lon", "label": "Lon", "kind": "protein", "description": "AAA+ protease degrading DnaA; induced, and allosterically activated by unfolded proteins, after DnaK loss or heat.", "refs": [ "10.1016/j.cell.2013.06.034", "10.1371/journal.pgen.1005342" ] } ], "edges": [ { "source": "MrrA", "target": "PhyK", "type": "phosphotransfer", "note": "PhyK accepts phosphoryl groups from MrrA", "refs": [ "10.1128/mbio.00809-18" ] }, { "source": "PhyK", "target": "PhyR", "type": "phosphotransfer", "note": "PhyK passes phosphate on to PhyR; PhyR phosphorylation is PhyK-dependent in vivo", "refs": [ "10.1128/mbio.00809-18", "10.1111/j.1365-2958.2011.07668.x" ] }, { "source": "MrrA", "target": "LovKR", "type": "phosphotransfer", "note": "MrrA also transfers phosphate to LovK", "refs": [ "10.1128/mbio.00809-18" ] }, { "source": "LovKR", "target": "PhyR", "type": "represses", "note": "LovK–LovR controls PhyR phosphorylation, draining phosphate away from the PhyK–PhyR branch", "refs": [ "10.1128/jb.00182-12", "10.1128/mbio.00809-18" ] }, { "source": "PhyR", "target": "NepR", "type": "binds", "note": "Phospho-PhyR's σ-like domain binds the anti-σ NepR (partner switch)", "refs": [ "10.1111/j.1365-2958.2010.07323.x", "10.1073/pnas.1116887109", "10.1111/j.1365-2958.2011.07668.x" ] }, { "source": "NepR", "target": "sigT", "type": "inhibits", "note": "NepR directly binds σT and negatively regulates its function", "refs": [ "10.1111/j.1365-2958.2011.07668.x" ] }, { "source": "sigT", "target": "GSR", "type": "activates-transcription", "note": "σT directly controls most of its regulon, induced e.g. by osmotic stress", "refs": [ "10.1111/j.1365-2958.2007.06005.x", "10.1111/j.1365-2958.2011.07668.x" ] }, { "source": "sigT", "target": "CtrA", "type": "represses", "note": "SigT mediates the carbon starvation-induced degradation of CtrA", "refs": [ "10.1371/journal.pone.0018179" ] }, { "source": "DNAdamage", "target": "LexA", "type": "inhibits", "note": "Damage-induced LexA cleavage releases repression of SOS genes", "refs": [ "10.1371/journal.pbio.1001977" ] }, { "source": "LexA", "target": "SidA", "type": "represses-transcription", "note": "sidA belongs to the LexA-regulated SOS regulon", "refs": [ "10.1101/gad.2038911", "10.1128/jb.01419-07" ] }, { "source": "DNAdamage", "target": "DidA", "type": "activates-transcription", "note": "didA is induced by DNA damage independently of SOS, via DriD", "refs": [ "10.1371/journal.pbio.1001977" ] }, { "source": "DNAdamage", "target": "CtrA", "type": "inhibits", "note": "DNA damage coordinately induces the SOS regulon and inhibits CtrA", "refs": [ "10.1101/gad.2038911" ] }, { "source": "SidA", "target": "FtsWN", "type": "inhibits", "note": "SidA binds FtsW directly, preventing final constriction", "refs": [ "10.1101/gad.2038911" ] }, { "source": "DidA", "target": "FtsWN", "type": "inhibits", "note": "DidA binds FtsN to block cytokinesis without disrupting divisome assembly", "refs": [ "10.1371/journal.pbio.1001977" ] }, { "source": "SpoT", "target": "ppGpp", "type": "synthesizes", "note": "SpoT synthesizes (p)ppGpp in response to carbon or nitrogen starvation", "refs": [ "10.1128/jb.00700-08", "10.1111/j.1365-2958.2011.07602.x", "10.1038/ncomms11423" ] }, { "source": "ppGpp", "target": "DnaA", "type": "promotes-degradation", "note": "SpoT/(p)ppGpp is required for starvation-triggered DnaA proteolysis in swarmer cells", "refs": [ "10.1128/jb.00700-08" ] }, { "source": "ppGpp", "target": "CtrA", "type": "stabilizes", "note": "ppGpp/polyP keep CtrA in starved swarmers; mutants degrade CtrA and start replication", "refs": [ "10.1128/jb.05932-11" ] }, { "source": "Lon", "target": "DnaA", "type": "degrades", "note": "Lon directly degrades DnaA; proteotoxic stress induces and activates Lon", "refs": [ "10.1016/j.cell.2013.06.034", "10.1371/journal.pgen.1005342" ] } ], "steps": [ { "label": "Stress sensing", "text": "Stress kinases phosphorylate MrrA, which passes phosphate via PhyK to PhyR; LovK–LovR siphons phosphate away.", "nodes": [ "MrrA", "PhyK", "PhyR", "LovKR" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "membrane", "label": "PhyK", "note": "Transmembrane sensor with a periplasmic cysteine (C95); acts as a phosphotransferase. Not at a specific site." }, { "kind": "cytoplasm", "labels": [ "MrrA", "PhyR", "LovK–LovR" ], "where": "whole", "note": "LovK is a soluble kinase (Foreman 2012); MrrA and PhyR locations are not established." } ], "caption": "General stress sensing: MrrA passes phosphate via the membrane protein PhyK to PhyR, while soluble LovK–LovR drains it away.", "refs": [ "10.1128/mbio.00809-18", "10.1128/jb.00182-12", "10.1111/j.1365-2958.2011.07668.x" ] } }, { "label": "Partner switch", "text": "Phospho-PhyR binds the anti-σ NepR, releasing σT to transcribe the general stress regulon.", "nodes": [ "PhyR", "NepR", "sigT", "GSR" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "cytoplasm", "labels": [ "PhyR", "NepR", "σT" ], "where": "whole", "note": "Phospho-PhyR's σ-like domain binds the anti-σ NepR, releasing σT." }, { "kind": "gene", "label": "*sigT*", "state": "on", "note": "Induced by osmotic stress in a σT-dependent manner (Alvarez-Martinez 2007)." }, { "kind": "gene", "label": "*sigU*", "state": "on", "note": "σT regulon member with the same ECF promoter motif (Alvarez-Martinez 2007)." } ], "caption": "Partner switch: phospho-PhyR captures NepR, freeing σT to transcribe its general stress regulon, including sigT and sigU.", "refs": [ "10.1073/pnas.1116887109", "10.1111/j.1365-2958.2010.07323.x", "10.1111/j.1365-2958.2011.07668.x", "10.1111/j.1365-2958.2007.06005.x" ] } }, { "label": "Starvation and CtrA", "text": "In carbon starvation σT also mediates CtrA degradation, uncoupling pole development from replication.", "nodes": [ "sigT", "CtrA" ], "scene": { "cell": "swarmer", "features": [ "flagellum" ], "marks": [ { "kind": "cytoplasm", "labels": [ "σT" ], "where": "whole" }, { "kind": "degraded", "label": "CtrA", "note": "SigT contributes to CtrA clearance in carbon-starved swarmers (Britos 2011); site of degradation not determined." } ], "caption": "Carbon-starved swarmer: σT mediates CtrA degradation (site not determined), uncoupling pole development from replication.", "refs": [ "10.1371/journal.pone.0018179" ] } }, { "label": "DNA damage", "text": "Damage relieves LexA repression (sidA), induces didA via DriD and inhibits CtrA; SidA (FtsW) and DidA (FtsN) hold division.", "nodes": [ "DNAdamage", "LexA", "SidA", "DidA", "FtsWN", "CtrA" ], "scene": { "cell": "predivisional", "features": [ "stalk" ], "marks": [ { "kind": "ring", "label": "Divisome", "note": "FtsZ ring and divisome assemble normally; SidA and DidA block only the final constriction." }, { "kind": "membrane", "at": "midcell", "label": "SidA", "note": "29-aa SOS-induced membrane protein that binds FtsW (Modell 2011)." }, { "kind": "focus", "at": "midcell", "label": "DidA", "note": "Binds the divisome protein FtsN without disrupting divisome assembly (Modell 2014); placed by its partner." }, { "kind": "gene", "label": "*sidA*", "state": "on", "note": "LexA-repressed SOS gene, induced after DNA damage." }, { "kind": "gene", "label": "*didA*", "state": "on", "note": "Induced by DNA damage independently of SOS, via DriD." } ], "caption": "After DNA damage sidA (SOS) and didA (via DriD) are induced; SidA binds FtsW and DidA binds FtsN to hold the assembled divisome.", "refs": [ "10.1101/gad.2038911", "10.1371/journal.pbio.1001977", "10.1128/jb.01419-07" ] } }, { "label": "Nutrient alarm", "text": "Carbon or nitrogen starvation triggers SpoT (p)ppGpp; starved swarmers stay in G1 and DnaA is cleared, so replication waits.", "nodes": [ "SpoT", "ppGpp", "DnaA", "CtrA" ], "scene": { "cell": "swarmer", "features": [ "flagellum" ], "marks": [ { "kind": "cytoplasm", "labels": [ "SpoT" ], "where": "whole", "note": "Ribosome-bound (p)ppGpp synthetase/hydrolase (Boutte 2011)." }, { "kind": "level", "label": "(p)ppGpp", "value": "high", "note": "SpoT-dependent rise on carbon starvation; swarmers make more ppGpp than stalked cells." }, { "kind": "degraded", "label": "DnaA", "note": "Starvation clears DnaA (SpoT-dependent; Lon proteolysis outpaces reduced translation); no site determined." } ], "caption": "Starved swarmer: SpoT makes (p)ppGpp, the cell stays in G1, and DnaA is cleared so replication cannot start.", "refs": [ "10.1128/jb.00700-08", "10.1128/jb.05932-11", "10.1111/j.1365-2958.2011.07602.x", "10.1111/j.1365-2958.2004.04459.x", "10.1371/journal.pgen.1005342" ] } }, { "label": "Proteotoxic stress", "text": "Heat or DnaK depletion induces and activates Lon, which degrades DnaA to arrest the cell cycle.", "nodes": [ "Lon", "DnaA" ], "scene": { "cell": "swarmer", "features": [], "marks": [ { "kind": "cytoplasm", "labels": [ "Lon" ], "where": "whole", "note": "Lon synthesis is induced and the protease is allosterically activated by unfolded proteins." }, { "kind": "degraded", "label": "DnaA", "note": "Lon directly degrades DnaA; no site determined." } ], "caption": "Heat or DnaK depletion: Lon is induced and activated by unfolded proteins, degrades DnaA, and the cell arrests in G1.", "refs": [ "10.1016/j.cell.2013.06.034" ] } } ], "refs": [ "10.1016/j.cell.2013.06.034", "10.1038/ncomms11423", "10.1073/pnas.0705887104", "10.1073/pnas.1116887109", "10.1101/gad.2038911", "10.1111/j.1365-2958.2004.04459.x", "10.1111/j.1365-2958.2007.06005.x", "10.1111/j.1365-2958.2010.07323.x", "10.1111/j.1365-2958.2011.07602.x", "10.1111/j.1365-2958.2011.07668.x", "10.1128/jb.00182-12", "10.1128/jb.00700-08", "10.1128/jb.01419-07", "10.1128/jb.05932-11", "10.1128/mbio.00809-18", "10.1371/journal.pbio.1001977", "10.1371/journal.pgen.1005342", "10.1371/journal.pone.0018179" ] }, { "id": "stalk-biogenesis", "title": "Stalk biogenesis and specialization", "summary": "The stalk is a thin extension of all envelope layers grown at the old pole after flagellum ejection. PopZ recruits SpmX, which recruits DivJ; bactofilins recruit the PG synthase PbpC, which anchors the stalk protein StpX, and diffusion barriers compartmentalize the stalk. PleD and ShkA–TacA/σ54 promote stalk growth; phosphate limitation lengthens it via Pst/PhoB.", "nodes": [ { "id": "PopZ", "label": "PopZ", "kind": "protein", "description": "Polar matrix; directly binds SpmX (bridging to DivJ) and affects polar stalk morphogenesis.", "refs": [ "10.1128/mbio.02238-16", "10.1016/j.cell.2008.07.016" ] }, { "id": "SpmX", "label": "SpmX", "kind": "protein", "description": "Lysozyme-homolog polarity protein; accumulates at the future stalked pole, oligomerizes and recruits/stimulates DivJ.", "refs": [ "10.1101/gad.1601808", "10.1128/mbio.02238-16" ] }, { "id": "DivJ", "label": "DivJ", "kind": "protein", "description": "Hand-off to core module: stalked-pole histidine kinase that phosphorylates DivK; recruited by SpmX.", "refs": [ "10.1101/gad.1601808", "10.1128/mbio.02238-16" ] }, { "id": "PleD", "label": "PleD", "kind": "protein", "description": "Diguanylate cyclase; without it only ~25% of cells build a stalk; constitutive PleD doubles stalk length.", "refs": [ "10.1046/j.1365-2958.1999.01358.x", "10.1046/j.1365-2958.2003.03401.x" ] }, { "id": "ShkA", "label": "ShkA", "kind": "protein", "description": "Hybrid histidine kinase heading the stalk phosphorelay; stimulated by c-di-GMP (c-di-GMP module).", "refs": [ "10.1111/j.1365-2958.2005.04970.x", "10.1038/s41467-020-14585-6" ] }, { "id": "ShpA", "label": "ShpA", "kind": "protein", "description": "Histidine phosphotransferase relaying phosphate from ShkA to TacA; required for stalk biogenesis.", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "id": "TacA", "label": "TacA", "kind": "protein", "description": "σ54-dependent activator required for cell-cycle-regulated stalk biogenesis.", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "id": "RpoN", "label": "σ54 (RpoN)", "kind": "protein", "description": "σ54; needed for both stalk and flagellum biogenesis; rpoN transcription rises with stalk formation.", "refs": [ "10.1101/gad.6.12a.2395", "10.1111/j.1365-2958.2005.04970.x" ] }, { "id": "StaR", "label": "StaR", "kind": "protein", "description": "TacA-regulon gene product that regulates stalk length.", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "id": "BacAB", "label": "BacA / BacB", "kind": "protein", "description": "Bactofilins: polymerizing, membrane-bound sheet near the stalked pole; scaffold for a stalk PG synthase.", "refs": [ "10.1038/emboj.2009.358", "10.7554/elife.100749" ] }, { "id": "PbpC", "label": "PbpC", "kind": "protein", "description": "Bifunctional PBP recruited by BacA; acts at the stalked pole in stalk synthesis and anchors StpX.", "refs": [ "10.1038/emboj.2009.358", "10.7554/elife.100749", "10.1111/mmi.12422", "10.1128/jb.01194-13" ] }, { "id": "StpX", "label": "StpX", "kind": "protein", "description": "Bitopic stalk membrane protein; modulates stalk elongation; PbpC-anchored; role in copper/zinc responses.", "refs": [ "10.1073/pnas.0909119107", "10.1111/mmi.12422" ] }, { "id": "barrier", "label": "Stalk diffusion barriers", "kind": "structure", "description": "Complexes of ≥4 proteins spanning the stalk that block protein exchange between stalk and cell body.", "refs": [ "10.1016/j.cell.2012.10.046" ] }, { "id": "Pst", "label": "PstSCAB", "kind": "gene-cluster", "description": "High-affinity phosphate transporter; pst mutants make long stalks; PstS (not PstA) is present in the stalk.", "refs": [ "10.1128/jb.182.2.337-347.2000", "10.1073/pnas.0602047103" ] }, { "id": "PhoB", "label": "PhoB", "kind": "protein", "description": "Pho regulon response regulator; required for stalk elongation in phosphate starvation and for pstS transcription.", "refs": [ "10.1128/jb.182.2.337-347.2000" ] }, { "id": "stalk", "label": "Stalk", "kind": "structure", "description": "Thin envelope extension at the old pole; takes up and hydrolyses organic phosphate; up to 30× longer in low phosphate.", "refs": [ "10.1128/jb.182.2.337-347.2000", "10.1073/pnas.0602047103", "10.1073/pnas.0909119107" ] } ], "edges": [ { "source": "PopZ", "target": "SpmX", "type": "recruits", "note": "PopZ directly recruits SpmX to the developing stalked pole", "refs": [ "10.1128/mbio.02238-16" ] }, { "source": "SpmX", "target": "DivJ", "type": "recruits", "note": "Localized SpmX recruits and stimulates the DivJ kinase", "refs": [ "10.1101/gad.1601808", "10.1128/mbio.02238-16" ] }, { "source": "PopZ", "target": "stalk", "type": "activates", "note": "PopZ affects polar stalk morphogenesis", "refs": [ "10.1016/j.cell.2008.07.016" ] }, { "source": "PleD", "target": "stalk", "type": "activates", "note": "pleD loss cuts stalk formation to ~25% of cells; constitutive PleD doubles stalk length", "refs": [ "10.1046/j.1365-2958.1999.01358.x", "10.1046/j.1365-2958.2003.03401.x" ] }, { "source": "ShkA", "target": "ShpA", "type": "phosphotransfer", "note": "Phosphotransfer profiling places ShpA downstream of the hybrid kinase ShkA", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "source": "ShpA", "target": "TacA", "type": "phosphotransfer", "note": "ShpA phosphorylates and thereby activates TacA in vivo", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "source": "TacA", "target": "StaR", "type": "activates-transcription", "note": "TacA activates its regulon, which includes staR", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "source": "RpoN", "target": "StaR", "type": "activates-transcription", "note": "TacA collaborates with σ54 to activate stalk gene expression", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "source": "StaR", "target": "stalk", "type": "activates", "note": "staR regulates stalk length", "refs": [ "10.1111/j.1365-2958.2005.04970.x" ] }, { "source": "BacAB", "target": "PbpC", "type": "recruits", "note": "Bactofilin polymerization and membrane binding are needed to recruit PbpC to the stalked pole", "refs": [ "10.1038/emboj.2009.358", "10.7554/elife.100749" ] }, { "source": "PbpC", "target": "stalk", "type": "synthesizes", "note": "Bactofilin-localized PG synthase acts at the stalked pole during stalk synthesis", "refs": [ "10.1038/emboj.2009.358", "10.1111/mmi.12422" ] }, { "source": "PbpC", "target": "StpX", "type": "localizes", "note": "PbpC anchors StpX to rigid outer-membrane components of the elongating stalk", "refs": [ "10.1111/mmi.12422" ] }, { "source": "StpX", "target": "stalk", "type": "localizes", "note": "StpX is sequestered in the stalk (dispersed in stalkless mutants) and modulates elongation", "refs": [ "10.1073/pnas.0909119107" ] }, { "source": "barrier", "target": "stalk", "type": "localizes", "note": "Barrier complexes prevent membrane and soluble protein exchange between stalk and body", "refs": [ "10.1016/j.cell.2012.10.046" ] }, { "source": "Pst", "target": "PhoB", "type": "represses", "note": "pst mutants make long stalks even in high phosphate, and this requires phoB", "refs": [ "10.1128/jb.182.2.337-347.2000" ] }, { "source": "PhoB", "target": "Pst", "type": "activates-transcription", "note": "pstS transcription depends on phoB", "refs": [ "10.1128/jb.182.2.337-347.2000" ] }, { "source": "PhoB", "target": "stalk", "type": "activates", "note": "PhoB is required for stalk elongation in response to phosphate starvation", "refs": [ "10.1128/jb.182.2.337-347.2000" ] } ], "steps": [ { "label": "Pole conversion", "text": "After flagellum ejection (flagellum module), SpmX accumulates on the PopZ matrix at the old pole and recruits DivJ.", "nodes": [ "PopZ", "SpmX", "DivJ" ], "scene": { "cell": "stalked", "features": [], "marks": [ { "kind": "focus", "at": "old-pole", "label": "PopZ" }, { "kind": "focus", "at": "old-pole", "label": "SpmX", "note": "Accumulates abruptly at the future stalked pole at G1→S" }, { "kind": "focus", "at": "old-pole", "label": "DivJ", "note": "Recruited and stimulated by SpmX" } ], "caption": "Newly differentiated cell: SpmX accumulates on the PopZ matrix at the old (future stalked) pole and recruits the DivJ kinase there.", "refs": [ "10.1101/gad.1601808", "10.1128/mbio.02238-16", "10.1016/j.cell.2008.07.016", "10.1083/jcb.201303036" ] } }, { "label": "Developmental signals", "text": "PleD and the ShkA→ShpA→TacA phosphorelay with σ54 switch on stalk genes such as staR.", "nodes": [ "PleD", "ShkA", "ShpA", "TacA", "RpoN", "StaR" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "nucleoid" }, { "kind": "level", "label": "c-di-GMP", "value": "high", "note": "Rising c-di-GMP stimulates ShkA at G1/S" }, { "kind": "focus", "at": "old-pole", "label": "PleD" }, { "kind": "cytoplasm", "labels": [ "ShkA", "ShpA", "TacA", "σ54" ], "where": "whole" }, { "kind": "gene", "label": "*staR*", "state": "on", "note": "TacA regulon gene that sets stalk length" } ], "caption": "At G1/S, rising c-di-GMP and PleD at the old pole drive the ShkA→ShpA→TacA relay; TacA with σ54 turns on stalk genes such as staR.", "refs": [ "10.1111/j.1365-2958.2005.04970.x", "10.1038/s41467-020-14585-6", "10.1101/gad.6.12a.2395", "10.1046/j.1365-2958.1999.01358.x", "10.1101/gad.289504", "10.1111/mmi.12777" ] } }, { "label": "Wall synthesis", "text": "Bactofilins BacA/BacB at the stalked pole recruit PbpC, which builds stalk wall and anchors StpX in the growing stalk.", "nodes": [ "BacAB", "PbpC", "StpX", "stalk" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "membrane", "at": "stalk-base", "label": "BacA/BacB", "note": "Bactofilin sheet lining the membrane near the stalked pole" }, { "kind": "membrane", "at": "stalk-base", "label": "PbpC", "note": "PG synthase recruited by bactofilins; acts at the stalked pole" }, { "kind": "membrane", "at": "stalk", "label": "StpX", "note": "Bitopic membrane protein retained in the stalk" } ], "caption": "Bactofilins BacA/BacB line the membrane at the stalked pole and recruit PbpC, which builds stalk wall and anchors StpX in the stalk.", "refs": [ "10.1038/emboj.2009.358", "10.7554/elife.100749", "10.1111/mmi.12422", "10.1073/pnas.0909119107" ] } }, { "label": "Compartmentalization", "text": "Diffusion-barrier complexes assemble across the stalk, keeping stalk and cell-body proteins apart.", "nodes": [ "barrier", "stalk" ], "scene": { "cell": "stalked", "features": [ "stalk" ], "marks": [ { "kind": "barrier", "label": "diffusion barrier", "note": "Complexes of at least four proteins spanning the stalk" } ], "caption": "Protein complexes span the stalk and block membrane and soluble proteins from moving between the stalk and the cell body.", "refs": [ "10.1016/j.cell.2012.10.046" ] } }, { "label": "Phosphate limitation", "text": "Low phosphate, signalled through Pst/PhoB, lengthens the stalk; PstS in the stalk binds phosphate while import occurs in the body.", "nodes": [ "Pst", "PhoB", "stalk" ], "scene": { "cell": "stalked", "features": [ "long-stalk" ], "marks": [ { "kind": "membrane", "at": "stalk", "label": "PstS", "note": "Periplasmic phosphate-binding protein found in the stalk (PstA is not)" }, { "kind": "cytoplasm", "labels": [ "PhoB" 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