title: Cyclic di-GMP mediates a histidine kinase/phosphatase switch by noncovalent domain cross-linking.
abstract: Histidine kinases are key components of regulatory networks in bacteria. Although many of these enzymes are bifunctional, mediating both phosphorylation and dephosphorylation of downstream targets, the molecular details of this central regulatory switch are unclear. We showed recently that the universal second messenger cyclic di-guanosine monophosphate (c-di-GMP) drives Caulobacter crescentus cell cycle progression by forcing the cell cycle kinase CckA from its default kinase into phosphatase mode. We use a combination of structure determination, modeling, and functional analysis to demonstrate that c-di-GMP reciprocally regulates the two antagonistic CckA activities through noncovalent cross-linking of the catalytic domain with the dimerization histidine phosphotransfer (DHp) domain. We demonstrate that both c-di-GMP and ADP (adenosine diphosphate) promote phosphatase activity and propose that c-di-GMP stabilizes the ADP-bound quaternary structure, which allows the receiver domain to access the dimeric DHp stem for dephosphorylation. In silico analyses predict that c-di-GMP control is widespread among bacterial histidine kinases, arguing that it can replace or modulate canonical transmembrane signaling.
authors.affiliation: Focal Area of Structural Biology and Biophysics, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Badri N
authors.initials: BN
authors.lastname: Dubey
authors.affiliation: Focal Area of Infection Biology, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Lori
authors.affiliation: Focal Area of Infection Biology, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: SIB Swiss Institute of Bioinformatics, sciCORE Computing Center, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Fucile
authors.affiliation: Focal Area of Structural Biology and Biophysics, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Plaza-Menacho
authors.affiliation: Focal Area of Infection Biology, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Urs
authors.identifier: 0000-0002-1637-3376
authors.initials: U
authors.lastname: Jenal
authors.affiliation: Focal Area of Structural Biology and Biophysics, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Tilman
authors.initials: T
authors.lastname: Schirmer
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D020134:Catalytic Domain; D016935:Caulobacter crescentus / Q000201:enzymology; D006152:Cyclic GMP / Q000737:chemistry*; D000071677:Histidine Kinase / Q000737:chemistry*; D008958:Models, Molecular; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D000244:Adenosine Diphosphate; D000071677:Histidine Kinase; D010744:Phosphoric Monoester Hydrolases; D006152:Cyclic GMP
keywords: Signaling; biochemistry; crystallography; cyclic di-GMP; histidine kinase; second messenger; signal transduction