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

Author

Listed:
  • 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
    University of Melbourne)

  • Michael Kuiper

    (CSIRO Data61)

  • Brit Winnen
  • 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
    The University of Adelaide)

  • Glenn F. King

    (The University of Queensland)

  • Timothy P. Stinear

    (University of Melbourne)

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.

Suggested Citation

  • 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, 2019. "Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10932-4
    DOI: 10.1038/s41467-019-10932-4
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