{
 "meta": {
  "organism": "Caulobacter crescentus (vibrioides) NA1000 taxid 565050 / CB15 taxid 190650",
  "schematic_note": "Phase activity table is a qualitative schematic compiled from the cited papers, not quantitative measurements.",
  "nonstandard_edge_types": {
   "encodes": "promoter node -> protein it produces",
   "initiates-replication": "DnaA -> Cori",
   "synthesizes": "diguanylate cyclase -> c-di-GMP",
   "hydrolyzes": "phosphodiesterase -> c-di-GMP"
  },
  "uniprot_field": "uniprot = NA1000 (565050) accession; uniprot_cb15 = CB15 (190650) accession where UniProt has a separate entry"
 },
 "nodes": [
  {
   "id": "DnaA",
   "label": "DnaA",
   "kind": "transcription-factor",
   "module": "master",
   "na1000": "CCNA_00008",
   "cb15": "CC_0008",
   "uniprot": "B8GWW5",
   "description": "Replication initiator that also acts as a transcription factor (gcrA, ftsZ, podJ); peaks at the G1-S transition.",
   "refs": [
    "10.1038/sj.emboj.7600927",
    "10.1111/j.1365-2958.2005.04912.x",
    "10.1016/j.cub.2011.05.040"
   ],
   "uniprot_cb15": "P0CAU4"
  },
  {
   "id": "GcrA",
   "label": "GcrA",
   "kind": "transcription-factor",
   "module": "master",
   "na1000": "CCNA_02328",
   "cb15": "CC_2245",
   "uniprot": "A0A0H3C9J4",
   "description": "Early-S master regulator; sigma70 cofactor whose activation favours CcrM-methylated (GANTC) promoters.",
   "refs": [
    "10.1126/science.1095191",
    "10.1101/gad.270660.115",
    "10.1371/journal.pgen.1003541"
   ]
  },
  {
   "id": "CtrA",
   "label": "CtrA",
   "kind": "response-regulator",
   "module": "master",
   "na1000": "CCNA_03130",
   "cb15": "CC_3035",
   "uniprot": "B8H358",
   "description": "Essential master response regulator; CtrA~P regulates ~100 genes and silences the replication origin in G1.",
   "refs": [
    "10.1016/s0092-8674(00)80995-2",
    "10.1073/pnas.062065699",
    "10.1073/pnas.95.1.120"
   ],
   "uniprot_cb15": "P0CAW8"
  },
  {
   "id": "CcrM",
   "label": "CcrM",
   "kind": "methyltransferase",
   "module": "master",
   "na1000": "CCNA_00382",
   "cb15": "CC_0378",
   "uniprot": "B8GZ33",
   "description": "GANTC adenine methyltransferase made at the end of S phase and degraded by Lon; remethylates the hemimethylated chromosome.",
   "refs": [
    "10.1073/pnas.93.3.1210",
    "10.1101/gad.10.12.1532",
    "10.1073/pnas.0708112104"
   ],
   "uniprot_cb15": "P0CAW2"
  },
  {
   "id": "SciP",
   "label": "SciP",
   "kind": "transcription-factor",
   "module": "master",
   "na1000": "CCNA_00948",
   "cb15": "CC_0903",
   "uniprot": "A0A0H3C507",
   "description": "Small CtrA inhibitory protein; accumulates in G1 swarmer cells, binds CtrA and represses CtrA-activated genes.",
   "refs": [
    "10.1016/j.molcel.2010.06.024",
    "10.1073/pnas.1014395107",
    "10.1111/mmi.12166"
   ]
  },
  {
   "id": "MucR1/2",
   "label": "MucR1/2",
   "kind": "transcription-factor",
   "module": "master",
   "na1000": "CCNA_00982; CCNA_00998",
   "cb15": "CC_0949",
   "uniprot": "A0A0H3C569; A0A0H3C684",
   "description": "Paralogous zinc-finger regulators that repress G1-phase genes in S phase, implementing the S-to-G1 transcriptional switch.",
   "refs": [
    "10.1038/ncomms5081",
    "10.1371/journal.pgen.1006499"
   ]
  },
  {
   "id": "Cori",
   "label": "Cori (origin)",
   "kind": "dna-site",
   "module": "master",
   "na1000": null,
   "cb15": null,
   "uniprot": null,
   "description": "Chromosome replication origin; DnaA initiates here, CtrA~P binds five sites to silence it, and PopZ anchors the ori/ParB complex at the pole.",
   "refs": [
    "10.1073/pnas.95.1.120",
    "10.1093/emboj/19.5.1138",
    "10.1016/j.cell.2008.07.015"
   ]
  },
  {
   "id": "DivJ",
   "label": "DivJ",
   "kind": "histidine-kinase",
   "module": "phosphorelay",
   "na1000": "CCNA_01116",
   "cb15": "CC_1063",
   "uniprot": "A0A0H3C5M8",
   "description": "Stalked-pole histidine kinase that phosphorylates DivK (and PleD); recruited and stimulated by SpmX.",
   "refs": [
    "10.1016/s1097-2765(00)80379-2",
    "10.1016/j.cell.2004.08.019",
    "10.1101/gad.1601808"
   ],
   "uniprot_cb15": "Q03228"
  },
  {
   "id": "PleC",
   "label": "PleC",
   "kind": "histidine-kinase",
   "module": "phosphorelay",
   "na1000": "CCNA_02567",
   "cb15": "CC_2482",
   "uniprot": "A0A0H3CCG1",
   "description": "Bifunctional kinase at the swarmer (flagellar) pole; acts as DivK~P phosphatase until DivK~P switches it to autokinase mode.",
   "refs": [
    "10.1016/s1097-2765(00)80379-2",
    "10.1016/j.cell.2004.08.019",
    "10.1016/j.cell.2008.02.045"
   ],
   "uniprot_cb15": "P37894"
  },
  {
   "id": "DivK",
   "label": "DivK",
   "kind": "response-regulator",
   "module": "phosphorelay",
   "na1000": "CCNA_02547",
   "cb15": "CC_2463",
   "uniprot": "A0A0H3C9D0",
   "description": "Essential single-domain response regulator; DivK~P allosterically regulates PleC/DivJ and inhibits DivL to shut off CckA.",
   "refs": [
    "10.1002/j.1460-2075.1995.tb00063.x",
    "10.1016/j.cell.2008.02.045",
    "10.1016/j.devcel.2011.01.007"
   ]
  },
  {
   "id": "PleD",
   "label": "PleD",
   "kind": "diguanylate-cyclase",
   "module": "phosphorelay",
   "na1000": "CCNA_02546",
   "cb15": "CC_2462",
   "uniprot": "B8GZM2",
   "description": "Response regulator with GGDEF output; phosphorylation drives dimerisation, polar localisation and c-di-GMP synthesis.",
   "refs": [
    "10.1101/gad.289504",
    "10.1074/jbc.m704702200",
    "10.1046/j.1365-2958.2003.03401.x"
   ],
   "uniprot_cb15": "Q9A5I5"
  },
  {
   "id": "DivL",
   "label": "DivL",
   "kind": "pseudokinase",
   "module": "phosphorelay",
   "na1000": "CCNA_03598",
   "cb15": "CC_3484",
   "uniprot": "A0A0H3CDI6",
   "description": "Tyrosine-containing pseudo-histidine kinase; senses DivK~P and promotes CckA localisation and kinase activity at the new pole.",
   "refs": [
    "10.1371/journal.pbio.1001979",
    "10.1073/pnas.1001767107",
    "10.1016/j.devcel.2011.01.007"
   ],
   "uniprot_cb15": "Q9RQQ9"
  },
  {
   "id": "CckA",
   "label": "CckA",
   "kind": "histidine-kinase",
   "module": "phosphorelay",
   "na1000": "CCNA_01132",
   "cb15": "CC_1078",
   "uniprot": "A0A0H3C8Q4",
   "description": "Essential bifunctional hybrid kinase/phosphatase initiating the CckA-ChpT-CtrA/CpdR phosphorelays; c-di-GMP flips it to phosphatase.",
   "refs": [
    "10.1016/s0092-8674(00)80719-9",
    "10.1128/jb.00992-09",
    "10.1038/nature14473"
   ],
   "uniprot_cb15": "H7C7G9"
  },
  {
   "id": "ChpT",
   "label": "ChpT",
   "kind": "phosphotransferase",
   "module": "phosphorelay",
   "na1000": "CCNA_03584",
   "cb15": "CC_3470",
   "uniprot": "A0A0H3CDR5",
   "description": "Essential histidine phosphotransferase relaying phosphate from CckA to both CtrA and CpdR.",
   "refs": [
    "10.1038/nature05321",
    "10.1016/j.devcel.2021.06.014"
   ]
  },
  {
   "id": "CpdR",
   "label": "CpdR",
   "kind": "response-regulator",
   "module": "phosphorelay",
   "na1000": "CCNA_00781",
   "cb15": "CC_0744",
   "uniprot": "A0A0H3C5J9",
   "description": "Single-domain response regulator and ClpXP adaptor; unphosphorylated CpdR localises ClpXP to the pole and primes CtrA degradation.",
   "refs": [
    "10.1073/pnas.0604554103",
    "10.1016/j.cell.2015.09.030",
    "10.1016/j.molcel.2011.07.018"
   ],
   "uniprot_cb15": "Q9AA62"
  },
  {
   "id": "PodJ",
   "label": "PodJ",
   "kind": "scaffold",
   "module": "polar",
   "na1000": "CCNA_02125",
   "cb15": "CC_2045",
   "uniprot": "B8GXA0",
   "description": "Polar localisation factor (PodJL/PodJS) required to target PleC (and pilus components) to the incipient swarmer pole.",
   "refs": [
    "10.1046/j.1365-2958.2003.03349.x",
    "10.1073/pnas.182411999",
    "10.1111/j.1365-2958.2012.08055.x"
   ],
   "uniprot_cb15": "Q9ZG88"
  },
  {
   "id": "SpmX",
   "label": "SpmX",
   "kind": "scaffold",
   "module": "polar",
   "na1000": "CCNA_02255",
   "cb15": "CC_2173",
   "uniprot": "A0A0H3C9Y4",
   "description": "Lysozyme-homolog polarity factor that bridges PopZ and DivJ, recruiting and stimulating DivJ at the stalked pole.",
   "refs": [
    "10.1101/gad.1601808",
    "10.1128/mbio.02238-16"
   ],
   "uniprot_cb15": "Q9A6C1"
  },
  {
   "id": "PopZ",
   "label": "PopZ",
   "kind": "scaffold",
   "module": "polar",
   "na1000": "CCNA_01380",
   "cb15": "CC_1319",
   "uniprot": "A0A0H3C7Y4",
   "description": "Self-assembling polar hub; anchors the ori/ParB complex and concentrates signalling proteins (CckA, ChpT, CtrA, DivJ, SpmX).",
   "refs": [
    "10.1016/j.cell.2008.07.015",
    "10.1016/j.cell.2008.07.016",
    "10.1073/pnas.1602380113"
   ]
  },
  {
   "id": "ClpXP",
   "label": "ClpXP",
   "kind": "protease",
   "module": "proteolysis",
   "na1000": "CCNA_02039; CCNA_02041",
   "cb15": "CC_1961; CC_1963",
   "uniprot": "B8GX14; B8GX16",
   "description": "Essential AAA+ protease (ClpX unfoldase + ClpP peptidase) that degrades CtrA at the G1-S transition, and PdeA.",
   "refs": [
    "10.1093/emboj/17.19.5658",
    "10.1016/j.cell.2005.12.033",
    "10.1016/j.cell.2015.09.030"
   ],
   "uniprot_cb15": "P0CAU2; P0CAU1"
  },
  {
   "id": "RcdA",
   "label": "RcdA",
   "kind": "adaptor",
   "module": "proteolysis",
   "na1000": "CCNA_03404",
   "cb15": "CC_3295",
   "uniprot": "A0A0H3CD07",
   "description": "ClpXP adaptor recruited by CpdR; required for CtrA polar localisation and degradation.",
   "refs": [
    "10.1016/j.cell.2005.12.033",
    "10.1073/pnas.1407862111",
    "10.1016/j.cell.2015.09.030"
   ]
  },
  {
   "id": "PopA",
   "label": "PopA",
   "kind": "adaptor",
   "module": "proteolysis",
   "na1000": "CCNA_01918",
   "cb15": "CC_1842",
   "uniprot": "A0A0H3C8I4",
   "description": "c-di-GMP effector; when bound to c-di-GMP it completes the CpdR-RcdA-PopA adaptor complex that delivers CtrA to ClpXP.",
   "refs": [
    "10.1101/gad.502409",
    "10.1073/pnas.1407862111",
    "10.1073/pnas.2024705118"
   ],
   "uniprot_cb15": "Q9A784"
  },
  {
   "id": "Lon",
   "label": "Lon",
   "kind": "protease",
   "module": "proteolysis",
   "na1000": "CCNA_02037",
   "cb15": "CC_1960",
   "uniprot": "B8GX12",
   "description": "ATP-dependent protease that constitutively degrades CcrM, degrades SciP at G1-S, and degrades DnaA (strongly under proteotoxic stress).",
   "refs": [
    "10.1101/gad.10.12.1532",
    "10.1111/mmi.12166",
    "10.1016/j.cell.2013.06.034"
   ],
   "uniprot_cb15": "P0CAW0"
  },
  {
   "id": "c-di-GMP",
   "label": "c-di-GMP",
   "kind": "second-messenger",
   "module": "proteolysis",
   "na1000": null,
   "cb15": null,
   "uniprot": null,
   "description": "Second messenger that rises at G1-S; activates PopA-mediated CtrA degradation and switches CckA from kinase to phosphatase.",
   "refs": [
    "10.1038/nature14473",
    "10.1101/gad.502409",
    "10.1371/journal.pgen.1003744"
   ]
  },
  {
   "id": "PdeA",
   "label": "PdeA",
   "kind": "phosphodiesterase",
   "module": "proteolysis",
   "na1000": "CCNA_03507",
   "cb15": "CC_3396",
   "uniprot": "A0A0H3CDG5",
   "description": "GGDEF/EAL phosphodiesterase that antagonises DgcB in G1; degraded by ClpXP via CpdR at the G1-S transition.",
   "refs": [
    "10.1016/j.molcel.2011.07.018"
   ],
   "uniprot_cb15": "Q9A310"
  },
  {
   "id": "DgcB",
   "label": "DgcB",
   "kind": "diguanylate-cyclase",
   "module": "proteolysis",
   "na1000": "CCNA_01926",
   "cb15": "CC_1850",
   "uniprot": "A0A0H3CAN8",
   "description": "Diguanylate cyclase whose activity is unopposed once PdeA is degraded, raising c-di-GMP with PleD at G1-S.",
   "refs": [
    "10.1016/j.molcel.2011.07.018"
   ],
   "uniprot_cb15": "Q9A776"
  },
  {
   "id": "ctrA-P1",
   "label": "ctrA P1",
   "kind": "dna-site",
   "module": "targets",
   "na1000": "CCNA_03130",
   "cb15": "CC_3035",
   "uniprot": null,
   "description": "Early-S ctrA promoter; activated by GcrA when hemimethylated, repressed by full GANTC methylation and by CtrA.",
   "refs": [
    "10.1073/pnas.96.12.6648",
    "10.1093/emboj/cdf490",
    "10.1073/pnas.0708112104"
   ]
  },
  {
   "id": "ctrA-P2",
   "label": "ctrA P2",
   "kind": "dna-site",
   "module": "targets",
   "na1000": "CCNA_03130",
   "cb15": "CC_3035",
   "uniprot": null,
   "description": "Stronger late-predivisional ctrA promoter under positive autoregulation by CtrA~P.",
   "refs": [
    "10.1073/pnas.96.12.6648",
    "10.1099/mic.0.055285-0",
    "10.1093/emboj/19.17.4503"
   ]
  },
  {
   "id": "ftsZ",
   "label": "ftsZ / FtsZ",
   "kind": "gene-module",
   "module": "targets",
   "na1000": "CCNA_02623",
   "cb15": "CC_2540",
   "uniprot": "B8H080",
   "description": "Division initiation gene; repressed by CtrA in swarmer cells, activated by DnaA and by CcrM methylation; FtsZ is degraded during division.",
   "refs": [
    "10.1101/gad.12.6.880",
    "10.1111/j.1365-2958.2005.04912.x",
    "10.1111/mmi.12180"
   ],
   "uniprot_cb15": "P0CAU9"
  },
  {
   "id": "ftsQA",
   "label": "ftsQA",
   "kind": "gene-module",
   "module": "targets",
   "na1000": "CCNA_02625; CCNA_02624",
   "cb15": "CC_2542; CC_2541",
   "uniprot": "B8H082; A0A0H3C9K0",
   "description": "Late cell-division operon transcribed from PQA at the end of DNA replication, activated by CtrA.",
   "refs": [
    "10.1046/j.1365-2958.1998.00753.x",
    "10.1093/emboj/19.17.4503"
   ],
   "uniprot_cb15": "P0CAU8; Q9A5B0"
  },
  {
   "id": "MipZ",
   "label": "MipZ",
   "kind": "gene-module",
   "module": "targets",
   "na1000": "CCNA_02246",
   "cb15": "CC_2165",
   "uniprot": "A0A0H3CA70",
   "description": "ParB-associated ATPase that inhibits FtsZ polymerisation near the poles, positioning the Z-ring at midcell; transcription promoted by CcrM.",
   "refs": [
    "10.1016/j.cell.2006.05.038",
    "10.1111/mmi.12180"
   ],
   "uniprot_cb15": "Q9A6C9"
  },
  {
   "id": "flagellar-class-II",
   "label": "Flagellar class II genes",
   "kind": "gene-module",
   "module": "targets",
   "na1000": null,
   "cb15": null,
   "uniprot": null,
   "description": "Early flagellar genes (e.g. fliF, fliQ) at the top of the flagellar hierarchy; activated by CtrA~P, co-repressed by SciP.",
   "refs": [
    "10.1016/s0092-8674(00)80995-2",
    "10.1073/pnas.95.4.1443",
    "10.1128/jb.181.8.2430-2439.1999"
   ]
  },
  {
   "id": "pilA",
   "label": "pilA",
   "kind": "gene-module",
   "module": "targets",
   "na1000": "CCNA_03043",
   "cb15": "CC_2948",
   "uniprot": "A0A0H3CAL4",
   "description": "Major pilin gene, transcribed late in the cell cycle under CtrA control; pili assemble at the swarmer pole.",
   "refs": [
    "10.1093/emboj/19.13.3223"
   ],
   "uniprot_cb15": "H7C7I2"
  },
  {
   "id": "chemotaxis",
   "label": "Chemotaxis genes",
   "kind": "gene-module",
   "module": "targets",
   "na1000": null,
   "cb15": null,
   "uniprot": null,
   "description": "Chemotaxis genes in the CtrA-SciP incoherent feed-forward regulon (activated by CtrA, repressed by SciP).",
   "refs": [
    "10.1073/pnas.1014395107"
   ]
  },
  {
   "id": "G1-genes",
   "label": "G1-phase genes",
   "kind": "gene-module",
   "module": "targets",
   "na1000": null,
   "cb15": null,
   "uniprot": null,
   "description": "Genes firing in G1/swarmer cells; repressed by MucR1/2 during S phase and released at the S-to-G1 switch.",
   "refs": [
    "10.1038/ncomms5081",
    "10.1371/journal.pgen.1006499"
   ]
  }
 ],
 "edges": [
  {
   "source": "DnaA",
   "target": "GcrA",
   "type": "activates-transcription",
   "note": "DnaA binds the gcrA promoter and is required for gcrA induction at G1-S.",
   "refs": [
    "10.1038/sj.emboj.7600927",
    "10.1111/j.1365-2958.2005.04912.x"
   ]
  },
  {
   "source": "DnaA",
   "target": "ftsZ",
   "type": "activates-transcription",
   "note": "His6-DnaA binds the ftsZ promoter; ftsZ is in the DnaA regulon.",
   "refs": [
    "10.1111/j.1365-2958.2005.04912.x"
   ]
  },
  {
   "source": "DnaA",
   "target": "PodJ",
   "type": "activates-transcription",
   "note": "His6-DnaA binds the podJ promoter; podJ is in the DnaA regulon.",
   "refs": [
    "10.1111/j.1365-2958.2005.04912.x"
   ]
  },
  {
   "source": "DnaA",
   "target": "Cori",
   "type": "initiates-replication",
   "note": "DnaA initiates chromosome replication at Cori; its activity oscillations set replication periodicity.",
   "refs": [
    "10.1073/pnas.0708112104",
    "10.1016/j.cub.2011.05.040",
    "10.1111/j.1365-2958.2004.04459.x"
   ]
  },
  {
   "source": "GcrA",
   "target": "ctrA-P1",
   "type": "activates-transcription",
   "note": "GcrA activates ctrA from P1 once the fork makes P1 hemimethylated; acts as a sigma70 cofactor at methylated promoters.",
   "refs": [
    "10.1038/sj.emboj.7600927",
    "10.1073/pnas.0708112104",
    "10.1101/gad.270660.115"
   ]
  },
  {
   "source": "CtrA",
   "target": "GcrA",
   "type": "represses-transcription",
   "note": "CtrA directly represses gcrA, opposing DnaA activation (G1 switch).",
   "refs": [
    "10.1038/sj.emboj.7600927",
    "10.1111/j.1365-2958.2005.04912.x",
    "10.1126/science.1095191"
   ]
  },
  {
   "source": "CtrA",
   "target": "ctrA-P1",
   "type": "represses-transcription",
   "note": "Negative feedback: CtrA footprints and represses the early P1 promoter.",
   "refs": [
    "10.1073/pnas.96.12.6648",
    "10.1099/mic.0.055285-0"
   ]
  },
  {
   "source": "CtrA",
   "target": "ctrA-P2",
   "type": "activates-transcription",
   "note": "Positive feedback: CtrA~P activates the strong late P2 promoter.",
   "refs": [
    "10.1073/pnas.96.12.6648",
    "10.1099/mic.0.055285-0",
    "10.1093/emboj/19.17.4503"
   ]
  },
  {
   "source": "ctrA-P1",
   "target": "CtrA",
   "type": "encodes",
   "note": "P1 transcript yields CtrA in early predivisional cells.",
   "refs": [
    "10.1073/pnas.96.12.6648"
   ]
  },
  {
   "source": "ctrA-P2",
   "target": "CtrA",
   "type": "encodes",
   "note": "P2 transcript yields the bulk of CtrA in late predivisional cells.",
   "refs": [
    "10.1073/pnas.96.12.6648"
   ]
  },
  {
   "source": "CtrA",
   "target": "Cori",
   "type": "binds-inhibits-origin",
   "note": "CtrA~P binds five origin sites overlapping a DnaA box and the strong promoter, silencing replication.",
   "refs": [
    "10.1073/pnas.95.1.120",
    "10.1093/emboj/19.5.1138",
    "10.1126/science.1095191"
   ]
  },
  {
   "source": "CtrA",
   "target": "CcrM",
   "type": "activates-transcription",
   "note": "CtrA~P binds PccrM (lower affinity than PfliQ) and activates ccrM late in S phase.",
   "refs": [
    "10.1128/jb.181.8.2430-2439.1999",
    "10.1073/pnas.0708112104",
    "10.1016/s0092-8674(00)80995-2"
   ]
  },
  {
   "source": "CtrA",
   "target": "flagellar-class-II",
   "type": "activates-transcription",
   "note": "Phospho-CtrA activates sigma73-dependent class II flagellar promoters (e.g. fliQ, fliF).",
   "refs": [
    "10.1016/s0092-8674(00)80995-2",
    "10.1073/pnas.95.4.1443",
    "10.1128/jb.181.8.2430-2439.1999"
   ]
  },
  {
   "source": "CtrA",
   "target": "pilA",
   "type": "activates-transcription",
   "note": "pilA transcription late in the cell cycle is regulated by CtrA.",
   "refs": [
    "10.1093/emboj/19.13.3223"
   ]
  },
  {
   "source": "CtrA",
   "target": "chemotaxis",
   "type": "activates-transcription",
   "note": "CtrA activates chemotaxis genes in the CtrA-SciP incoherent feed-forward loop.",
   "refs": [
    "10.1073/pnas.1014395107"
   ]
  },
  {
   "source": "CtrA",
   "target": "ftsZ",
   "type": "represses-transcription",
   "note": "CtrA binds over the ftsZ start site and represses it in swarmer cells.",
   "refs": [
    "10.1101/gad.12.6.880",
    "10.1093/emboj/19.17.4503"
   ]
  },
  {
   "source": "CtrA",
   "target": "ftsQA",
   "type": "activates-transcription",
   "note": "CtrA activates the PQA promoter of ftsQA, a replication checkpoint on division.",
   "refs": [
    "10.1093/emboj/19.17.4503"
   ]
  },
  {
   "source": "CtrA",
   "target": "SciP",
   "type": "activates-transcription",
   "note": "CtrA activates sciP (first arm of an incoherent feed-forward loop).",
   "refs": [
    "10.1073/pnas.1014395107"
   ]
  },
  {
   "source": "CtrA",
   "target": "DivK",
   "type": "activates-transcription",
   "note": "CtrA binds the divK promoter and induces DivK synthesis, feeding back to downregulate CckA.",
   "refs": [
    "10.1038/nature05321",
    "10.1073/pnas.202495099"
   ]
  },
  {
   "source": "CtrA",
   "target": "PodJ",
   "type": "represses-transcription",
   "note": "CAVEAT: deleting the CtrA site in PpodJ raises activity, so CtrA lowers podJ level; timing is CtrA-independent.",
   "refs": [
    "10.1128/jb.181.13.3967-3973.1999"
   ]
  },
  {
   "source": "SciP",
   "target": "CtrA",
   "type": "inhibits",
   "note": "SciP binds CtrA without changing its stability or phosphorylation, likely blocking RNAP recruitment.",
   "refs": [
    "10.1016/j.molcel.2010.06.024"
   ]
  },
  {
   "source": "SciP",
   "target": "CtrA",
   "type": "represses-transcription",
   "note": "SciP represses ctrA transcription (negative feedback lowering peak CtrA).",
   "refs": [
    "10.1073/pnas.1014395107"
   ]
  },
  {
   "source": "SciP",
   "target": "flagellar-class-II",
   "type": "represses-transcription",
   "note": "SciP binds its own motif in CtrA/SciP co-regulated flagellar promoters.",
   "refs": [
    "10.1073/pnas.1014395107"
   ]
  },
  {
   "source": "SciP",
   "target": "chemotaxis",
   "type": "represses-transcription",
   "note": "SciP represses CtrA-activated chemotaxis genes.",
   "refs": [
    "10.1073/pnas.1014395107"
   ]
  },
  {
   "source": "MucR1/2",
   "target": "G1-genes",
   "type": "represses-transcription",
   "note": "MucR1/2 repress G1-specific promoters during S phase (S-to-G1 switch module).",
   "refs": [
    "10.1038/ncomms5081",
    "10.1371/journal.pgen.1006499"
   ]
  },
  {
   "source": "CcrM",
   "target": "ctrA-P1",
   "type": "methylates",
   "note": "P1 GANTC full methylation represses it; fork passage makes it hemimethylated and active.",
   "refs": [
    "10.1093/emboj/cdf490",
    "10.1073/pnas.0708112104"
   ]
  },
  {
   "source": "CcrM",
   "target": "DnaA",
   "type": "methylates",
   "note": "dnaA is preferentially transcribed from a fully methylated promoter (methylation ratchet).",
   "refs": [
    "10.1073/pnas.0708112104"
   ]
  },
  {
   "source": "CcrM",
   "target": "ftsZ",
   "type": "methylates",
   "note": "Methylated CGACTC motif promotes ftsZ transcription (full > hemi > unmethylated).",
   "refs": [
    "10.1111/mmi.12180"
   ]
  },
  {
   "source": "CcrM",
   "target": "MipZ",
   "type": "methylates",
   "note": "CcrM methylation promotes mipZ transcription via a CGACTC motif.",
   "refs": [
    "10.1111/mmi.12180"
   ]
  },
  {
   "source": "CcrM",
   "target": "Cori",
   "type": "methylates",
   "note": "CAVEAT: ori region stays hemimethylated longest; methylation is not required to control initiation.",
   "refs": [
    "10.1128/jb.181.7.1984-1993.1999",
    "10.1093/nar/gkt1352"
   ]
  },
  {
   "source": "DivJ",
   "target": "DivK",
   "type": "phosphorylates",
   "note": "DivJ at the stalked pole phosphorylates DivK, generating DivK~P.",
   "refs": [
    "10.1073/pnas.95.4.1443",
    "10.1016/j.cell.2004.08.019",
    "10.1101/gad.1601808"
   ]
  },
  {
   "source": "PleC",
   "target": "DivK",
   "type": "dephosphorylates",
   "note": "PleC at the swarmer pole acts as a DivK~P phosphatase; with DivJ it drives DivK pole-to-pole shuttling.",
   "refs": [
    "10.1002/j.1460-2075.1995.tb00063.x",
    "10.1016/j.cell.2004.08.019",
    "10.1016/j.cell.2008.02.045"
   ]
  },
  {
   "source": "DivK",
   "target": "PleC",
   "type": "allosteric-activation",
   "note": "DivK~P binds PleC and switches it from phosphatase to autokinase (drives c-di-GMP program).",
   "refs": [
    "10.1016/j.cell.2008.02.045"
   ]
  },
  {
   "source": "DivK",
   "target": "DivJ",
   "type": "allosteric-activation",
   "note": "DivK allosterically stimulates DivJ autokinase, promoting its own phosphorylation.",
   "refs": [
    "10.1016/j.cell.2008.02.045"
   ]
  },
  {
   "source": "DivK",
   "target": "DivL",
   "type": "inhibits",
   "note": "DivK~P binds DivL (PAS domains select DivK~P), inhibiting DivL-dependent CckA activation.",
   "refs": [
    "10.1016/j.devcel.2011.01.007",
    "10.1371/journal.pbio.1001979"
   ]
  },
  {
   "source": "DivL",
   "target": "CckA",
   "type": "allosteric-activation",
   "note": "DivL recruits CckA to the new pole and promotes its autophosphorylation (independent of DivL kinase activity).",
   "refs": [
    "10.1073/pnas.1001767107",
    "10.1016/j.devcel.2011.01.007"
   ]
  },
  {
   "source": "CckA",
   "target": "ChpT",
   "type": "phosphorylates",
   "note": "CckA autophosphorylates and transfers phosphate to ChpT, initiating two phosphorelays.",
   "refs": [
    "10.1038/nature05321",
    "10.1128/jb.00992-09"
   ]
  },
  {
   "source": "ChpT",
   "target": "CtrA",
   "type": "phosphotransfer",
   "note": "ChpT~P phosphorylates (and stabilises) CtrA.",
   "refs": [
    "10.1038/nature05321",
    "10.1038/s41564-019-0647-7"
   ]
  },
  {
   "source": "ChpT",
   "target": "CpdR",
   "type": "phosphotransfer",
   "note": "ChpT~P phosphorylates CpdR, inactivating it as a ClpXP adaptor.",
   "refs": [
    "10.1038/nature05321",
    "10.1073/pnas.0604554103"
   ]
  },
  {
   "source": "CckA",
   "target": "CtrA",
   "type": "dephosphorylates",
   "note": "In phosphatase mode CckA drains CtrA~P (reverse flow via ChpT) before replication initiation.",
   "refs": [
    "10.1128/jb.00992-09",
    "10.1038/nature14473"
   ]
  },
  {
   "source": "c-di-GMP",
   "target": "CckA",
   "type": "inhibits",
   "note": "c-di-GMP binds CckA's PAS-B domain, inhibiting kinase and stimulating phosphatase activity.",
   "refs": [
    "10.1038/nature14473",
    "10.1038/ncomms11454"
   ]
  },
  {
   "source": "DivJ",
   "target": "PleD",
   "type": "phosphorylates",
   "note": "DivJ positively controls PleD phosphorylation in vivo, activating the cyclase.",
   "refs": [
    "10.1046/j.1365-2958.2003.03401.x",
    "10.1016/j.cell.2008.02.045"
   ]
  },
  {
   "source": "PleD",
   "target": "c-di-GMP",
   "type": "synthesizes",
   "note": "Phosphorylation-driven PleD dimers condense GTP into c-di-GMP at the differentiating pole.",
   "refs": [
    "10.1101/gad.289504",
    "10.1074/jbc.m704702200"
   ]
  },
  {
   "source": "DgcB",
   "target": "c-di-GMP",
   "type": "synthesizes",
   "note": "DgcB synthesises c-di-GMP; unopposed after PdeA degradation at G1-S.",
   "refs": [
    "10.1016/j.molcel.2011.07.018"
   ]
  },
  {
   "source": "PdeA",
   "target": "c-di-GMP",
   "type": "hydrolyzes",
   "note": "Phosphodiesterase PdeA antagonises DgcB-derived c-di-GMP in G1.",
   "refs": [
    "10.1016/j.molcel.2011.07.018"
   ]
  },
  {
   "source": "c-di-GMP",
   "target": "PopA",
   "type": "allosteric-activation",
   "note": "c-di-GMP binding to PopA is required for polar sequestration and CtrA-adaptor function.",
   "refs": [
    "10.1101/gad.502409",
    "10.1073/pnas.1407862111",
    "10.1073/pnas.2024705118"
   ]
  },
  {
   "source": "PopA",
   "target": "CtrA",
   "type": "promotes-degradation",
   "note": "c-di-GMP-bound PopA binds CtrA receiver helix 1 and, via RcdA, delivers it to ClpXP.",
   "refs": [
    "10.1101/gad.502409",
    "10.1073/pnas.1407862111",
    "10.1016/j.cell.2015.09.030"
   ]
  },
  {
   "source": "RcdA",
   "target": "CtrA",
   "type": "promotes-degradation",
   "note": "RcdA complexes with CtrA and ClpX; required for CtrA polar localisation and degradation.",
   "refs": [
    "10.1016/j.cell.2005.12.033",
    "10.1073/pnas.1407862111"
   ]
  },
  {
   "source": "CpdR",
   "target": "CtrA",
   "type": "promotes-degradation",
   "note": "Unphosphorylated CpdR is required for CtrA proteolysis (adaptor with RcdA and PopA~c-di-GMP).",
   "refs": [
    "10.1073/pnas.0604554103",
    "10.1073/pnas.1407862111"
   ]
  },
  {
   "source": "CpdR",
   "target": "ClpXP",
   "type": "localizes",
   "note": "Unphosphorylated CpdR binds ClpXP and localises it to the stalked pole; CpdR~P delocalises it.",
   "refs": [
    "10.1073/pnas.0604554103",
    "10.1016/j.cell.2015.09.030"
   ]
  },
  {
   "source": "CpdR",
   "target": "RcdA",
   "type": "localizes",
   "note": "CpdR-primed ClpXP recruits the RcdA adaptor (adaptor hierarchy).",
   "refs": [
    "10.1016/j.cell.2015.09.030"
   ]
  },
  {
   "source": "CpdR",
   "target": "PdeA",
   "type": "promotes-degradation",
   "note": "CpdR delivers PdeA to ClpXP in a phosphorylation-dependent manner.",
   "refs": [
    "10.1016/j.molcel.2011.07.018"
   ]
  },
  {
   "source": "ClpXP",
   "target": "CtrA",
   "type": "promotes-degradation",
   "note": "ClpXP degrades CtrA at the G1-S transition and in the stalked compartment.",
   "refs": [
    "10.1093/emboj/17.19.5658",
    "10.1016/j.cell.2005.12.033",
    "10.1073/pnas.0402153101"
   ]
  },
  {
   "source": "ClpXP",
   "target": "PdeA",
   "type": "promotes-degradation",
   "note": "PdeA is degraded by ClpXP at the G1-S transition.",
   "refs": [
    "10.1016/j.molcel.2011.07.018"
   ]
  },
  {
   "source": "Lon",
   "target": "CcrM",
   "type": "promotes-degradation",
   "note": "Lon constitutively degrades CcrM, restricting it to predivisional cells.",
   "refs": [
    "10.1101/gad.10.12.1532"
   ]
  },
  {
   "source": "Lon",
   "target": "SciP",
   "type": "promotes-degradation",
   "note": "Lon degrades SciP at the G1-S transition.",
   "refs": [
    "10.1111/mmi.12166"
   ]
  },
  {
   "source": "Lon",
   "target": "DnaA",
   "type": "promotes-degradation",
   "note": "Lon directly degrades DnaA; shown upon proteotoxic stress (DnaK depletion).",
   "refs": [
    "10.1016/j.cell.2013.06.034"
   ]
  },
  {
   "source": "PodJ",
   "target": "PleC",
   "type": "localizes",
   "note": "PodJ is required to target PleC to the incipient swarmer pole.",
   "refs": [
    "10.1046/j.1365-2958.2003.03349.x",
    "10.1073/pnas.182411999"
   ]
  },
  {
   "source": "SpmX",
   "target": "DivJ",
   "type": "localizes",
   "note": "SpmX recruits DivJ to the stalked pole and stimulates its activity.",
   "refs": [
    "10.1101/gad.1601808",
    "10.1128/mbio.02238-16"
   ]
  },
  {
   "source": "PopZ",
   "target": "SpmX",
   "type": "localizes",
   "note": "PopZ directly binds and recruits SpmX, which bridges to DivJ.",
   "refs": [
    "10.1128/mbio.02238-16"
   ]
  },
  {
   "source": "PopZ",
   "target": "DivJ",
   "type": "localizes",
   "note": "PopZ mediates DivJ polar localisation (via the SpmX bridge).",
   "refs": [
    "10.1016/j.cell.2008.07.016",
    "10.1128/mbio.02238-16"
   ]
  },
  {
   "source": "PopZ",
   "target": "CckA",
   "type": "localizes",
   "note": "PopZ mediates CckA polar localisation; the PopZ microdomain enhances CckA signalling.",
   "refs": [
    "10.1016/j.cell.2008.07.016",
    "10.1038/s41564-019-0647-7"
   ]
  },
  {
   "source": "PopZ",
   "target": "ChpT",
   "type": "localizes",
   "note": "ChpT enters the PopZ microdomain once ParA arrives at the new pole with the replicated chromosome.",
   "refs": [
    "10.1016/j.devcel.2021.06.014",
    "10.1038/s41564-019-0647-7"
   ]
  },
  {
   "source": "PopZ",
   "target": "CtrA",
   "type": "localizes",
   "note": "CtrA entry into the polar PopZ microdomain requires a PopZ binding pathway; creates a CtrA~P gradient.",
   "refs": [
    "10.1038/s41564-019-0647-7"
   ]
  },
  {
   "source": "PopZ",
   "target": "Cori",
   "type": "localizes",
   "note": "PopZ binds ParB and tethers the origin-proximal ParB/parS complex at the cell pole.",
   "refs": [
    "10.1016/j.cell.2008.07.015",
    "10.1016/j.cell.2008.07.016"
   ]
  },
  {
   "source": "MipZ",
   "target": "ftsZ",
   "type": "inhibits",
   "note": "MipZ directly interferes with FtsZ polymerisation, restricting the Z-ring to midcell.",
   "refs": [
    "10.1016/j.cell.2006.05.038"
   ]
  }
 ],
 "phases": [
  {
   "id": "swarmer-g1",
   "label": "Swarmer cell (G1)",
   "active": [
    "CtrA",
    "SciP",
    "PleC",
    "CckA",
    "ChpT",
    "DivL",
    "PdeA",
    "PodJ"
   ],
   "inactive": [
    "DivJ",
    "GcrA",
    "CcrM",
    "MucR1/2",
    "Cori"
   ],
   "note": "CtrA~P silences Cori; SciP blocks CtrA-activated genes. PleC (phosphatase, flagellar pole) keeps DivK unphosphorylated so CckA kinase stays on; CpdR~P keeps ClpXP off.",
   "refs": [
    "10.1073/pnas.95.1.120",
    "10.1016/j.molcel.2010.06.024",
    "10.1016/s1097-2765(00)80379-2",
    "10.1016/j.devcel.2011.01.007",
    "10.1073/pnas.0604554103",
    "10.1016/j.molcel.2011.07.018",
    "10.1371/journal.pgen.1006499"
   ]
  },
  {
   "id": "g1-s-transition",
   "label": "G1-S transition (swarmer-to-stalked)",
   "active": [
    "DnaA",
    "DivJ",
    "SpmX",
    "DivK",
    "PleD",
    "DgcB",
    "c-di-GMP",
    "PopA",
    "CpdR",
    "RcdA",
    "ClpXP",
    "Lon",
    "PopZ"
   ],
   "inactive": [
    "CtrA",
    "SciP",
    "PdeA",
    "PleC",
    "CckA"
   ],
   "note": "SpmX-DivJ raise DivK~P; PdeA is degraded and PleD/DgcB raise c-di-GMP, flipping CckA to phosphatase. Unphosphorylated CpdR+RcdA+PopA send CtrA to ClpXP; Lon clears SciP; DnaA peaks.",
   "refs": [
    "10.1101/gad.1601808",
    "10.1016/j.molcel.2011.07.018",
    "10.1038/nature14473",
    "10.1073/pnas.0604554103",
    "10.1073/pnas.1407862111",
    "10.1111/mmi.12166",
    "10.1038/sj.emboj.7600927",
    "10.1016/s1097-2765(00)80379-2"
   ]
  },
  {
   "id": "early-s",
   "label": "Early S phase (stalked)",
   "active": [
    "DnaA",
    "GcrA",
    "ctrA-P1",
    "ftsZ",
    "DivJ",
    "MucR1/2",
    "Cori"
   ],
   "inactive": [
    "CtrA",
    "CcrM",
    "SciP"
   ],
   "note": "DnaA initiates at Cori and induces gcrA; GcrA then fires ctrA P1 once the fork makes it hemimethylated. ftsZ transcription switches on with replication; MucR1/2 repress G1 genes in S phase.",
   "refs": [
    "10.1038/sj.emboj.7600927",
    "10.1073/pnas.0708112104",
    "10.1126/science.1095191",
    "10.1093/emboj/cdf490",
    "10.1101/gad.12.6.880",
    "10.1038/ncomms5081",
    "10.1371/journal.pgen.1006499"
   ]
  },
  {
   "id": "late-s-predivisional",
   "label": "Late S / predivisional cell",
   "active": [
    "CtrA",
    "ctrA-P2",
    "CckA",
    "DivL",
    "ChpT",
    "CcrM",
    "ftsQA",
    "flagellar-class-II",
    "pilA",
    "SciP",
    "PleC",
    "PodJ",
    "PopZ"
   ],
   "inactive": [
    "DnaA",
    "GcrA",
    "ctrA-P1"
   ],
   "note": "DivL recruits CckA to the new pole; ChpT enters the PopZ zone when ParA arrives. CtrA~P re-accumulates via P2, represses P1 and gcrA, and activates ccrM, ftsQA, class II flagellar genes and sciP.",
   "refs": [
    "10.1073/pnas.1001767107",
    "10.1016/j.devcel.2021.06.014",
    "10.1073/pnas.96.12.6648",
    "10.1038/sj.emboj.7600927",
    "10.1073/pnas.0708112104",
    "10.1046/j.1365-2958.1998.00753.x",
    "10.1093/emboj/19.17.4503",
    "10.1073/pnas.1014395107",
    "10.1046/j.1365-2958.2003.03349.x"
   ]
  },
  {
   "id": "pd-swarmer-compartment",
   "label": "Predivisional — swarmer compartment",
   "active": [
    "CtrA",
    "CckA",
    "DivL",
    "ChpT",
    "PleC",
    "SciP",
    "pilA",
    "PodJ"
   ],
   "inactive": [
    "DivJ",
    "Cori"
   ],
   "note": "PleC phosphatase at the swarmer pole shields DivL-CckA from DivK~P; polar CckA-ChpT signalling within PopZ yields a CtrA~P gradient highest in this half. SciP accumulates preferentially here.",
   "refs": [
    "10.1016/j.cell.2004.08.019",
    "10.1016/j.devcel.2011.01.007",
    "10.1073/pnas.1015397108",
    "10.1038/s41564-019-0647-7",
    "10.1073/pnas.1014395107",
    "10.1093/emboj/19.13.3223"
   ]
  },
  {
   "id": "pd-stalked-compartment",
   "label": "Predivisional — stalked compartment",
   "active": [
    "DivJ",
    "SpmX",
    "DivK",
    "c-di-GMP",
    "CpdR",
    "RcdA",
    "PopA",
    "ClpXP",
    "PopZ"
   ],
   "inactive": [
    "CtrA",
    "PleC",
    "CckA"
   ],
   "note": "DivJ (stalked pole) keeps DivK~P high, inhibiting DivL-CckA; asymmetric c-di-GMP holds CckA in phosphatase mode; CtrA is recruited to the stalked pole and degraded, licensing immediate re-initiation.",
   "refs": [
    "10.1016/s1097-2765(00)80379-2",
    "10.1016/j.devcel.2011.01.007",
    "10.1038/nature14473",
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    "10.1073/pnas.0402153101",
    "10.1073/pnas.1015397108"
   ]
  },
  {
   "id": "division",
   "label": "Cell division",
   "active": [
    "ftsZ",
    "MipZ",
    "ftsQA",
    "Lon",
    "MucR1/2"
   ],
   "inactive": [
    "CcrM"
   ],
   "note": "MipZ gradients place the FtsZ ring at midcell; FtsQA act late. Cytokinesis separates PleC and DivJ, ending DivK shuttling and fixing daughter fates. CcrM is degraded by Lon before division; MucR1/2 mediate the S-to-G1 switch.",
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