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https://hdl.handle.net/2440/122882
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Type: | Journal article |
Title: | Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus |
Author: | Monk, I.R. Shaikh, N. Begg, S.L. Gajdiss, M. Sharkey, L.K.R. Lee, J.Y.H. Pidot, S.J. Seemann, T. Kuiper, M. Winnen, B. Hvorup, R. Collins, B.M. Bierbaum, G. Udagedara, S.R. Morey, J.R. Pulyani, N. Howden, B.P. Maher, M.J. McDevitt, C.A. King, G.F. et al. |
Citation: | Nature Communications, 2019; 10(1):1-13 |
Publisher: | Springer Nature |
Issue Date: | 2019 |
ISSN: | 2041-1723 2041-1723 |
Statement of Responsibility: | 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, Timothy P. Stinear |
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. |
Keywords: | Staphylococcus aureus Cations, Divalent Zinc Tyrosine Histidine Bacterial Proteins Amino Acid Substitution Mutation Regulon Molecular Dynamics Simulation Histidine Kinase Protein Serine-Threonine Kinases |
Rights: | © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
DOI: | 10.1038/s41467-019-10932-4 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/GNT1010776 http://purl.org/au-research/grants/nhmrc/GNT1044414 http://purl.org/au-research/grants/nhmrc/GNT1142695 http://purl.org/au-research/grants/nhmrc/GNT1136021 http://purl.org/au-research/grants/nhmrc/GNT1049192 http://purl.org/au-research/grants/nhmrc/GNT1129589 http://purl.org/au-research/grants/nhmrc/GNT1145075 http://purl.org/au-research/grants/nhmrc/GNT1105525 http://purl.org/au-research/grants/nhmrc/GNT1105905 http://purl.org/au-research/grants/arc/DP170102102 http://purl.org/au-research/grants/arc/FT170100006 |
Published version: | http://dx.doi.org/10.1038/s41467-019-10932-4 |
Appears in Collections: | Aurora harvest 8 Microbiology and Immunology publications |
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