Journal article

Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus

Ian R Monk, Nausad Shaikh, Stephanie L Begg, Mike Gajdiss, Liam KR Sharkey, Jean YH Lee, Sacha J Pidot, Torsten Seemann, Michael Kuiper, Brit Winnen, Rikki Hvorup, Brett M Collins, Gabriele Bierbaum, Saumya R Udagedara, Jacqueline R Morey, Neha Pulyani, Benjamin P Howden, Megan J Maher, Christopher A McDevitt, Glenn F King Show all



WalKR (YycFG) is the only essential two-component regulator in the human pathogen Staphylococcus aureus. WalKR regulates peptidoglycan synthesis, but this function alone does not explain its essentiality. Here, to further understand WalKR function, we investigate a suppressor mutant that arose when WalKR activity was impaired; a histidine to tyrosine substitution (H271Y) in the cytoplasmic Per-Arnt-Sim (PASCYT) domain of the histidine kinase WalK. Introducing the WalKH271Y mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PASCYT domain reveal a metal-binding site, in which a zinc ion (Zn2+) is tetrahedrally-coordinated by four amino acids includin..

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Awarded by Australian National Health and Medical Research Council

Awarded by Australian Research Council

Funding Acknowledgements

We acknowledge funding from the Australian National Health and Medical Research Council (Project Grant GNT1010776 and Principal Research Fellowship GNT1044414 to G.F.K.; Early Career Research Fellowship GNT1142695 to S.L.B., Senior Research Fellowship GNT1136021 to B.M.C.; Project Grants GNT1049192, GNT1129589 and GNT1145075 and Senior Research Fellowship GNT1105525 to T.P.S.; and Practioner Research Fellowship GNT1105905 to B.P.H.) and the Australian Research Council (Discovery Project DP170102102 and Future Fellowship FT170100006 to C.A.M.). Aspects of this research were undertaken on the Macromolecular Crystallography beamline MX2 at the Australian Synchrotron (Victoria, Australia) and we thank the beamline staff for their enthusiastic and professional support.