Molecular Playground/CheA
In Progress: One of the CBI Molecules being studied in the University of Massachusetts Amherst Chemistry-Biology Interface Program at UMass Amherst. <Structure load='1b3q' size='500' frame='true' align='right' caption='Structure of histidine kinase CheA, 1b3q' scene='User:Elizabeth_R._Haglin/Sandbox_1/P3p4p5/3'>
Biological contextBiological context
Histidine Kinase (HK) CheA relays signals from the transmembrane chemoreceptors (methyl-accepting chemotaxis proteins/MCPs) to regulate bacterial chemotaxis. The functional form of CheA exists as a dimer and is associated to the receptors through a coupling protein CheW. Kinase activity of CheA depends on signals received from the receptor via an ATP-dependent phosphoryl transfer the trans monomer of dimeric CheA. The phosphoryl group is subsequently transferred to the response regulator (RR) CheY and carried throughout the cell to interact with the flagellar motor and control cellular mobility and directionality.
Chemotaxis is a behavior used by most motile flagellated bacteria,like E. coli and T. maritima, to modify their swimming pattern in response to environmental stimuli. Directionality is controlled by the counter-clockwise (CCW) running or clockwise (CW) tumbling motion of the flagellar motor, which in turn is regulated by large arrays of a two-component signal transduction complex responsible for sensing extracellular chemical concentration gradients. Upon binding of a chemical ligand, the MCPs regulate ATP-dependent trans-autophosphorylation activity of the histidine kinase CheA. A repellent binding event leads to increases in phosphorylated CheA (CheA-P) and a subsequent increase in phosphorylation of CheA’s binding partner and CheY. Phosphorylated CheY (CheY-P) has a high affinity for the flagellar motor switch protein FliM and at increased concentrations will change the motor rotation from CCW to CW, leading to tumbling. Likewise, attractant binding inhibits CheA phosphorylation so unphosphorylated CheY dominates, the motor switch CCW motion is unaffected, and the cell maintains smooth swimming. The CheY-P signal is additionally regulated by the phosphatase CheZ. Ultimately, the flux of phosphoryl groups governs the mobility response to external stimuli.
StructureStructure
CheA exists as a homodimer of 71-kDa subunits. Each monomer catalyzes an ATP-dependent trans-phosphorylation of a histidine. A monomer contains five domains (P1-P5 from N- to C-terminus) connected by highly dynamic linkers of various lengths. Each domain has a distinct function.Due to the size of CheA, the solved structures available to date do not have all five domains. The PDB files included in this proteopedia page are with a dimer of P3P4P5 and which contains a P1P2-CheY complex.
- P1: histidine phosphotransfer domain (HPt) mediates phosphate transfer from ATP to CheY
- P2: CheY binding domain releases CheY-P upon small conformational changes
- P3: dimerization domain
- P4: ATP-binding catalytic domain
- P5: autophosphorylation regulatory domain relays signal input to P4 from the chemoreceptor and CheW
P1P2: Histidine phosphotransfer domainsP1P2: Histidine phosphotransfer domains
P3P4P5: Kinase core domainsP3P4P5: Kinase core domains
Binding partnersBinding partners
Additional 3D structures of CheAAdditional 3D structures of CheA
ReferencesReferences
- ↑ Wadhams GH, Armitage JP. Making sense of it all: bacterial chemotaxis. Nat Rev Mol Cell Biol. 2004 Dec;5(12):1024-37. PMID:15573139 doi:10.1038/nrm1524
- ↑ Mo G, Zhou H, Kawamura T, Dahlquist FW. Solution structure of a complex of the histidine autokinase CheA with its substrate CheY. Biochemistry. 2012 May 8;51(18):3786-98. Epub 2012 Apr 26. PMID:22494339 doi:10.1021/bi300147m