Network
The cell-cycle circuit
Four master regulators, DnaA, GcrA, CtrA and the methyltransferase CcrM, switch on in sequence, and each one helps turn on the next. A phosphorelay that starts at the cell poles decides where CtrA is active and where it is destroyed. Select any component or arrow to see the evidence; play the cycle to see which regulators are active when.
Showing every interaction. Choose a phase to see which regulators are active.
The interactive diagram needs JavaScript; every interaction is also listed below.
Every interaction and its evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| DnaA | activates transcription | GcrA | DnaA binds the gcrA promoter and is required for gcrA induction at G1-S. | Collier et al. 2006; Hottes et al. 2005 |
| DnaA | activates transcription | ftsZ / FtsZ | His6-DnaA binds the ftsZ promoter; ftsZ is in the DnaA regulon. | Hottes et al. 2005 |
| DnaA | activates transcription | PodJ | His6-DnaA binds the podJ promoter; podJ is in the DnaA regulon. | Hottes et al. 2005 |
| DnaA | initiates replication at | Cori (origin) | DnaA initiates chromosome replication at Cori; its activity oscillations set replication periodicity. | Collier et al. 2007; Jonas et al. 2011; Gorbatyuk et al. 2005 |
| GcrA | activates transcription | ctrA P1 | GcrA activates ctrA from P1 once the fork makes P1 hemimethylated; acts as a sigma70 cofactor at methylated promoters. | Collier et al. 2006; Collier et al. 2007; Haakonsen et al. 2015 |
| CtrA | represses transcription | GcrA | CtrA directly represses gcrA, opposing DnaA activation (G1 switch). | Collier et al. 2006; Hottes et al. 2005; Holtzendorff et al. 2004 |
| CtrA | represses transcription | ctrA P1 | Negative feedback: CtrA footprints and represses the early P1 promoter. | Domian et al. 1999; Schredl et al. 2012 |
| CtrA | activates transcription | ctrA P2 | Positive feedback: CtrA~P activates the strong late P2 promoter. | Domian et al. 1999; Schredl et al. 2012; Wortinger et al. 2000 |
| ctrA P1 | promoter of | CtrA | P1 transcript yields CtrA in early predivisional cells. | Domian et al. 1999 |
| ctrA P2 | promoter of | CtrA | P2 transcript yields the bulk of CtrA in late predivisional cells. | Domian et al. 1999 |
| CtrA | binds and silences the origin | Cori (origin) | CtrA~P binds five origin sites overlapping a DnaA box and the strong promoter, silencing replication. | Quon et al. 1998; Siam et al. 2000; Holtzendorff et al. 2004 |
| CtrA | activates transcription | CcrM | CtrA~P binds PccrM (lower affinity than PfliQ) and activates ccrM late in S phase. | Reisenauer et al. 1999; Collier et al. 2007; Quon et al. 1996 |
| CtrA | activates transcription | Flagellar class II genes | Phospho-CtrA activates sigma73-dependent class II flagellar promoters (e.g. fliQ, fliF). | Quon et al. 1996; Wu et al. 1998; Reisenauer et al. 1999 |
| CtrA | activates transcription | pilA | pilA transcription late in the cell cycle is regulated by CtrA. | Skerker & Shapiro 2000 |
| CtrA | activates transcription | Chemotaxis genes | CtrA activates chemotaxis genes in the CtrA-SciP incoherent feed-forward loop. | Tan et al. 2010 |
| CtrA | represses transcription | ftsZ / FtsZ | CtrA binds over the ftsZ start site and represses it in swarmer cells. | Kelly et al. 1998; Wortinger et al. 2000 |
| CtrA | activates transcription | ftsQA | CtrA activates the PQA promoter of ftsQA, a replication checkpoint on division. | Wortinger et al. 2000 |
| CtrA | activates transcription | SciP | CtrA activates sciP (first arm of an incoherent feed-forward loop). | Tan et al. 2010 |
| CtrA | activates transcription | DivK | CtrA binds the divK promoter and induces DivK synthesis, feeding back to downregulate CckA. | Biondi et al. 2006; Hung et al. 2002 |
| CtrA | represses transcription | PodJ | CAVEAT: deleting the CtrA site in PpodJ raises activity, so CtrA lowers podJ level; timing is CtrA-independent. | Crymes et al. 1999 |
| SciP | inhibits | CtrA | SciP binds CtrA without changing its stability or phosphorylation, likely blocking RNAP recruitment. | Gora et al. 2010 |
| SciP | represses transcription | CtrA | SciP represses ctrA transcription (negative feedback lowering peak CtrA). | Tan et al. 2010 |
| SciP | represses transcription | Flagellar class II genes | SciP binds its own motif in CtrA/SciP co-regulated flagellar promoters. | Tan et al. 2010 |
| SciP | represses transcription | Chemotaxis genes | SciP represses CtrA-activated chemotaxis genes. | Tan et al. 2010 |
| MucR1/2 | represses transcription | G1-phase genes | MucR1/2 repress G1-specific promoters during S phase (S-to-G1 switch module). | Fumeaux et al. 2014; Ardissone et al. 2016 |
| CcrM | methylates | ctrA P1 | P1 GANTC full methylation represses it; fork passage makes it hemimethylated and active. | Reisenauer et al. 2002; Collier et al. 2007 |
| CcrM | methylates | DnaA | dnaA is preferentially transcribed from a fully methylated promoter (methylation ratchet). | Collier et al. 2007 |
| CcrM | methylates | ftsZ / FtsZ | Methylated CGACTC motif promotes ftsZ transcription (full > hemi > unmethylated). | Gonzalez et al. 2013 |
| CcrM | methylates | MipZ | CcrM methylation promotes mipZ transcription via a CGACTC motif. | Gonzalez et al. 2013 |
| CcrM | methylates | Cori (origin) | CAVEAT: ori region stays hemimethylated longest; methylation is not required to control initiation. | Marczynski et al. 1999; Gonzalez et al. 2014 |
| DivJ | phosphorylates | DivK | DivJ at the stalked pole phosphorylates DivK, generating DivK~P. | Wu et al. 1998; Matroule et al. 2004; Radhakrishnan et al. 2008 |
| PleC | dephosphorylates | DivK | PleC at the swarmer pole acts as a DivK~P phosphatase; with DivJ it drives DivK pole-to-pole shuttling. | Hecht et al. 1995; Matroule et al. 2004; Paul et al. 2008 |
| DivK | allosteric activation | PleC | DivK~P binds PleC and switches it from phosphatase to autokinase (drives c-di-GMP program). | Paul et al. 2008 |
| DivK | allosteric activation | DivJ | DivK allosterically stimulates DivJ autokinase, promoting its own phosphorylation. | Paul et al. 2008 |
| DivK | inhibits | DivL | DivK~P binds DivL (PAS domains select DivK~P), inhibiting DivL-dependent CckA activation. | Tsokos et al. 2011; Childers et al. 2014 |
| DivL | allosteric activation | CckA | DivL recruits CckA to the new pole and promotes its autophosphorylation (independent of DivL kinase activity). | Iniesta et al. 2010; Tsokos et al. 2011 |
| CckA | phosphorylates | ChpT | CckA autophosphorylates and transfers phosphate to ChpT, initiating two phosphorelays. | Biondi et al. 2006; Chen et al. 2009 |
| ChpT | phosphotransfer | CtrA | ChpT~P phosphorylates (and stabilises) CtrA. | Biondi et al. 2006; Lasker et al. 2020 |
| ChpT | phosphotransfer | CpdR | ChpT~P phosphorylates CpdR, inactivating it as a ClpXP adaptor. | Biondi et al. 2006; Iniesta et al. 2006 |
| CckA | dephosphorylates | CtrA | In phosphatase mode CckA drains CtrA~P (reverse flow via ChpT) before replication initiation. | Chen et al. 2009; Lori et al. 2015 |
| c-di-GMP | inhibits | CckA | c-di-GMP binds CckA's PAS-B domain, inhibiting kinase and stimulating phosphatase activity. | Lori et al. 2015; Mann et al. 2016 |
| DivJ | phosphorylates | PleD | DivJ positively controls PleD phosphorylation in vivo, activating the cyclase. | Aldridge et al. 2003; Paul et al. 2008 |
| PleD | synthesizes | c-di-GMP | Phosphorylation-driven PleD dimers condense GTP into c-di-GMP at the differentiating pole. | Paul et al. 2004; Paul et al. 2007 |
| DgcB | synthesizes | c-di-GMP | DgcB synthesises c-di-GMP; unopposed after PdeA degradation at G1-S. | Abel et al. 2011 |
| PdeA | hydrolyzes | c-di-GMP | Phosphodiesterase PdeA antagonises DgcB-derived c-di-GMP in G1. | Abel et al. 2011 |
| c-di-GMP | allosteric activation | PopA | c-di-GMP binding to PopA is required for polar sequestration and CtrA-adaptor function. | Duerig et al. 2009; Smith et al. 2014; Wang et al. 2021 |
| PopA | promotes degradation | CtrA | c-di-GMP-bound PopA binds CtrA receiver helix 1 and, via RcdA, delivers it to ClpXP. | Duerig et al. 2009; Smith et al. 2014; Joshi et al. 2015 |
| RcdA | promotes degradation | CtrA | RcdA complexes with CtrA and ClpX; required for CtrA polar localisation and degradation. | McGrath et al. 2006; Smith et al. 2014 |
| CpdR | promotes degradation | CtrA | Unphosphorylated CpdR is required for CtrA proteolysis (adaptor with RcdA and PopA~c-di-GMP). | Iniesta et al. 2006; Smith et al. 2014 |
| CpdR | localizes / scaffolds | ClpXP | Unphosphorylated CpdR binds ClpXP and localises it to the stalked pole; CpdR~P delocalises it. | Iniesta et al. 2006; Joshi et al. 2015 |
| CpdR | localizes / scaffolds | RcdA | CpdR-primed ClpXP recruits the RcdA adaptor (adaptor hierarchy). | Joshi et al. 2015 |
| CpdR | promotes degradation | PdeA | CpdR delivers PdeA to ClpXP in a phosphorylation-dependent manner. | Abel et al. 2011 |
| ClpXP | promotes degradation | CtrA | ClpXP degrades CtrA at the G1-S transition and in the stalked compartment. | Jenal & Fuchs 1998; McGrath et al. 2006; Ryan et al. 2004 |
| ClpXP | promotes degradation | PdeA | PdeA is degraded by ClpXP at the G1-S transition. | Abel et al. 2011 |
| Lon | promotes degradation | CcrM | Lon constitutively degrades CcrM, restricting it to predivisional cells. | Wright et al. 1996 |
| Lon | promotes degradation | SciP | Lon degrades SciP at the G1-S transition. | Gora et al. 2013 |
| Lon | promotes degradation | DnaA | Lon directly degrades DnaA; shown upon proteotoxic stress (DnaK depletion). | Jonas et al. 2013 |
| PodJ | localizes / scaffolds | PleC | PodJ is required to target PleC to the incipient swarmer pole. | Hinz et al. 2003; Viollier et al. 2002 |
| SpmX | localizes / scaffolds | DivJ | SpmX recruits DivJ to the stalked pole and stimulates its activity. | Radhakrishnan et al. 2008; Perez et al. 2017 |
| PopZ | localizes / scaffolds | SpmX | PopZ directly binds and recruits SpmX, which bridges to DivJ. | Perez et al. 2017 |
| PopZ | localizes / scaffolds | DivJ | PopZ mediates DivJ polar localisation (via the SpmX bridge). | Ebersbach et al. 2008; Perez et al. 2017 |
| PopZ | localizes / scaffolds | CckA | PopZ mediates CckA polar localisation; the PopZ microdomain enhances CckA signalling. | Ebersbach et al. 2008; Lasker et al. 2020 |
| PopZ | localizes / scaffolds | ChpT | ChpT enters the PopZ microdomain once ParA arrives at the new pole with the replicated chromosome. | Guzzo et al. 2021; Lasker et al. 2020 |
| PopZ | localizes / scaffolds | CtrA | CtrA entry into the polar PopZ microdomain requires a PopZ binding pathway; creates a CtrA~P gradient. | Lasker et al. 2020 |
| PopZ | localizes / scaffolds | Cori (origin) | PopZ binds ParB and tethers the origin-proximal ParB/parS complex at the cell pole. | Bowman et al. 2008; Ebersbach et al. 2008 |
| MipZ | inhibits | ftsZ / FtsZ | MipZ directly interferes with FtsZ polymerisation, restricting the Z-ring to midcell. | Thanbichler & Shapiro 2006 |
Components
| Component | Role | NA1000 | CB15 | UniProt |
|---|---|---|---|---|
| DnaA | Replication initiator that also acts as a transcription factor (gcrA, ftsZ, podJ); peaks at the G1-S transition. | CCNA_00008 | CC_0008 | B8GWW5 |
| GcrA | Early-S master regulator; sigma70 cofactor whose activation favours CcrM-methylated (GANTC) promoters. | CCNA_02328 | CC_2245 | A0A0H3C9J4 |
| CtrA | Essential master response regulator; CtrA~P regulates ~100 genes and silences the replication origin in G1. | CCNA_03130 | CC_3035 | B8H358 |
| CcrM | GANTC adenine methyltransferase made at the end of S phase and degraded by Lon; remethylates the hemimethylated chromosome. | CCNA_00382 | CC_0378 | B8GZ33 |
| SciP | Small CtrA inhibitory protein; accumulates in G1 swarmer cells, binds CtrA and represses CtrA-activated genes. | CCNA_00948 | CC_0903 | A0A0H3C507 |
| MucR1/2 | Paralogous zinc-finger regulators that repress G1-phase genes in S phase, implementing the S-to-G1 transcriptional switch. | CCNA_00982 CCNA_00998 | CC_0949 | A0A0H3C569 A0A0H3C684 |
| Cori (origin) | Chromosome replication origin; DnaA initiates here, CtrA~P binds five sites to silence it, and PopZ anchors the ori/ParB complex at the pole. | — | — | — |
| DivJ | Stalked-pole histidine kinase that phosphorylates DivK (and PleD); recruited and stimulated by SpmX. | CCNA_01116 | CC_1063 | A0A0H3C5M8 |
| PleC | Bifunctional kinase at the swarmer (flagellar) pole; acts as DivK~P phosphatase until DivK~P switches it to autokinase mode. | CCNA_02567 | CC_2482 | A0A0H3CCG1 |
| DivK | Essential single-domain response regulator; DivK~P allosterically regulates PleC/DivJ and inhibits DivL to shut off CckA. | CCNA_02547 | CC_2463 | A0A0H3C9D0 |
| PleD | Response regulator with GGDEF output; phosphorylation drives dimerisation, polar localisation and c-di-GMP synthesis. | CCNA_02546 | CC_2462 | B8GZM2 |
| DivL | Tyrosine-containing pseudo-histidine kinase; senses DivK~P and promotes CckA localisation and kinase activity at the new pole. | CCNA_03598 | CC_3484 | A0A0H3CDI6 |
| CckA | Essential bifunctional hybrid kinase/phosphatase initiating the CckA-ChpT-CtrA/CpdR phosphorelays; c-di-GMP flips it to phosphatase. | CCNA_01132 | CC_1078 | A0A0H3C8Q4 |
| ChpT | Essential histidine phosphotransferase relaying phosphate from CckA to both CtrA and CpdR. | CCNA_03584 | CC_3470 | A0A0H3CDR5 |
| CpdR | Single-domain response regulator and ClpXP adaptor; unphosphorylated CpdR localises ClpXP to the pole and primes CtrA degradation. | CCNA_00781 | CC_0744 | A0A0H3C5J9 |
| PodJ | Polar localisation factor (PodJL/PodJS) required to target PleC (and pilus components) to the incipient swarmer pole. | CCNA_02125 | CC_2045 | B8GXA0 |
| SpmX | Lysozyme-homolog polarity factor that bridges PopZ and DivJ, recruiting and stimulating DivJ at the stalked pole. | CCNA_02255 | CC_2173 | A0A0H3C9Y4 |
| PopZ | Self-assembling polar hub; anchors the ori/ParB complex and concentrates signalling proteins (CckA, ChpT, CtrA, DivJ, SpmX). | CCNA_01380 | CC_1319 | A0A0H3C7Y4 |
| ClpXP | Essential AAA+ protease (ClpX unfoldase + ClpP peptidase) that degrades CtrA at the G1-S transition, and PdeA. | CCNA_02039 CCNA_02041 | CC_1961 CC_1963 | B8GX14 B8GX16 |
| RcdA | ClpXP adaptor recruited by CpdR; required for CtrA polar localisation and degradation. | CCNA_03404 | CC_3295 | A0A0H3CD07 |
| PopA | c-di-GMP effector; when bound to c-di-GMP it completes the CpdR-RcdA-PopA adaptor complex that delivers CtrA to ClpXP. | CCNA_01918 | CC_1842 | A0A0H3C8I4 |
| Lon | ATP-dependent protease that constitutively degrades CcrM, degrades SciP at G1-S, and degrades DnaA (strongly under proteotoxic stress). | CCNA_02037 | CC_1960 | B8GX12 |
| c-di-GMP | Second messenger that rises at G1-S; activates PopA-mediated CtrA degradation and switches CckA from kinase to phosphatase. | — | — | — |
| PdeA | GGDEF/EAL phosphodiesterase that antagonises DgcB in G1; degraded by ClpXP via CpdR at the G1-S transition. | CCNA_03507 | CC_3396 | A0A0H3CDG5 |
| DgcB | Diguanylate cyclase whose activity is unopposed once PdeA is degraded, raising c-di-GMP with PleD at G1-S. | CCNA_01926 | CC_1850 | A0A0H3CAN8 |
| ctrA P1 | Early-S ctrA promoter; activated by GcrA when hemimethylated, repressed by full GANTC methylation and by CtrA. | CCNA_03130 | CC_3035 | — |
| ctrA P2 | Stronger late-predivisional ctrA promoter under positive autoregulation by CtrA~P. | CCNA_03130 | CC_3035 | — |
| ftsZ / FtsZ | Division initiation gene; repressed by CtrA in swarmer cells, activated by DnaA and by CcrM methylation; FtsZ is degraded during division. | CCNA_02623 | CC_2540 | B8H080 |
| ftsQA | Late cell-division operon transcribed from PQA at the end of DNA replication, activated by CtrA. | CCNA_02625 CCNA_02624 | CC_2542 CC_2541 | B8H082 A0A0H3C9K0 |
| MipZ | ParB-associated ATPase that inhibits FtsZ polymerisation near the poles, positioning the Z-ring at midcell; transcription promoted by CcrM. | CCNA_02246 | CC_2165 | A0A0H3CA70 |
| Flagellar class II genes | Early flagellar genes (e.g. fliF, fliQ) at the top of the flagellar hierarchy; activated by CtrA~P, co-repressed by SciP. | — | — | — |
| pilA | Major pilin gene, transcribed late in the cell cycle under CtrA control; pili assemble at the swarmer pole. | CCNA_03043 | CC_2948 | A0A0H3CAL4 |
| Chemotaxis genes | Chemotaxis genes in the CtrA-SciP incoherent feed-forward regulon (activated by CtrA, repressed by SciP). | — | — | — |
| G1-phase genes | Genes firing in G1/swarmer cells; repressed by MucR1/2 during S phase and released at the S-to-G1 switch. | — | — | — |