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

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.

authors

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

publication date

  • 2019