Histidine kinase regulation by a cyclophilin-like inhibitor |
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Authors: | Jacques David A Langley David B Jeffries Cy M Cunningham Katherine A Burkholder William F Guss J Mitchell Trewhella Jill |
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Affiliation: | 1 School of Molecular and Microbial Biosciences, University of Sydney, Sydney, New South Wales 2006, Australia 2 Department of Biological Sciences, Stanford University, 371 Serra Mall, Stanford, CA 94305, USA |
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Abstract: | The sensor histidine kinase A (KinA) from Bacillus subtilis triggers a phosphorelay that activates sporulation. The antikinase KipI prevents sporulation by binding KinA and inhibiting the autophosphorylation reaction. Using neutron contrast variation, mutagenesis, and fluorescence data, we show that two KipI monomers bind via their C-domains at a conserved proline in the KinA dimerization and histidine-phosphotransfer (DHp) domain. Our crystal structure of the KipI C-domain reveals the binding motif has a distinctive hydrophobic groove formed by a five-stranded antiparallel β-sheet; a characteristic of the cyclophilin family of proteins that bind prolines and often act as cis-trans peptidyl-prolyl isomerases. We propose that the DHp domain of KinA transmits conformational signals to regulate kinase activity via this proline-mediated interaction. Given that both KinA and KipI homologues are widespread in the bacterial kingdom, this mechanism has broad significance in bacterial signal transduction. |
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Keywords: | KinA, histidine kinase A DHp, dimerization and histidine phosphotransfer CA, catalytic and ATP-binding KipI, kinase inhibitor protein Sda, suppressor of dnaA GST, glutathione S-transferase AI-2, autoinducer-2 TCEP, tris(2-carboxyethyl)-phosphine hydrochloride |
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