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 K. R. Sharkey, Jean Y. H. 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 and Timothy P. Stinear ()
Additional contact information
Ian R. Monk: University of Melbourne
Nausad Shaikh: The University of Queensland
Stephanie L. Begg: University of Melbourne
Mike Gajdiss: University Clinics of Bonn, Institute of Medical Microbiology, Immunology and Parasitology
Liam K. R. Sharkey: University of Melbourne
Jean Y. H. Lee: University of Melbourne
Sacha J. Pidot: University of Melbourne
Torsten Seemann: University of Melbourne
Michael Kuiper: CSIRO Data61
Rikki Hvorup: The University of Queensland
Brett M. Collins: The University of Queensland
Gabriele Bierbaum: University Clinics of Bonn, Institute of Medical Microbiology, Immunology and Parasitology
Saumya R. Udagedara: La Trobe University
Jacqueline R. Morey: The University of Adelaide
Neha Pulyani: La Trobe University
Benjamin P. Howden: University of Melbourne
Megan J. Maher: La Trobe University
Christopher A. McDevitt: University of Melbourne
Glenn F. King: The University of Queensland
Timothy P. Stinear: University of Melbourne

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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 including H271. The WalKH271Y mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn2+-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn2+ sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon.

Date: 2019
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DOI: 10.1038/s41467-019-10932-4

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