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

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...

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Autores principales: Monk, Ian R., Shaikh, Nausad, Begg, Stephanie L., Gajdiss, Mike, Sharkey, Liam K. R., Lee, Jean Y. H., Pidot, Sacha J., Seemann, Torsten, Kuiper, Michael, Winnen, Brit, Hvorup, Rikki, Collins, Brett M., Bierbaum, Gabriele, Udagedara, Saumya R., Morey, Jacqueline R., Pulyani, Neha, Howden, Benjamin P., Maher, Megan J., McDevitt, Christopher A., King, Glenn F., Stinear, Timothy P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624279/
https://www.ncbi.nlm.nih.gov/pubmed/31296851
http://dx.doi.org/10.1038/s41467-019-10932-4
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author Monk, Ian R.
Shaikh, Nausad
Begg, Stephanie L.
Gajdiss, Mike
Sharkey, Liam K. R.
Lee, Jean Y. H.
Pidot, Sacha J.
Seemann, Torsten
Kuiper, Michael
Winnen, Brit
Hvorup, Rikki
Collins, Brett M.
Bierbaum, Gabriele
Udagedara, Saumya R.
Morey, Jacqueline R.
Pulyani, Neha
Howden, Benjamin P.
Maher, Megan J.
McDevitt, Christopher A.
King, Glenn F.
Stinear, Timothy P.
author_facet Monk, Ian R.
Shaikh, Nausad
Begg, Stephanie L.
Gajdiss, Mike
Sharkey, Liam K. R.
Lee, Jean Y. H.
Pidot, Sacha J.
Seemann, Torsten
Kuiper, Michael
Winnen, Brit
Hvorup, Rikki
Collins, Brett M.
Bierbaum, Gabriele
Udagedara, Saumya R.
Morey, Jacqueline R.
Pulyani, Neha
Howden, Benjamin P.
Maher, Megan J.
McDevitt, Christopher A.
King, Glenn F.
Stinear, Timothy P.
author_sort Monk, Ian R.
collection PubMed
description 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 (PAS(CYT)) domain of the histidine kinase WalK. Introducing the WalK(H271Y) mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PAS(CYT) domain reveal a metal-binding site, in which a zinc ion (Zn(2+)) is tetrahedrally-coordinated by four amino acids including H271. The WalK(H271Y) mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn(2+)-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn(2+) sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon.
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spelling pubmed-66242792019-07-15 Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus Monk, Ian R. Shaikh, Nausad Begg, Stephanie L. Gajdiss, Mike Sharkey, Liam K. R. Lee, Jean Y. H. Pidot, Sacha J. Seemann, Torsten Kuiper, Michael Winnen, Brit Hvorup, Rikki Collins, Brett M. Bierbaum, Gabriele Udagedara, Saumya R. Morey, Jacqueline R. Pulyani, Neha Howden, Benjamin P. Maher, Megan J. McDevitt, Christopher A. King, Glenn F. Stinear, Timothy P. Nat Commun Article 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 (PAS(CYT)) domain of the histidine kinase WalK. Introducing the WalK(H271Y) mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PAS(CYT) domain reveal a metal-binding site, in which a zinc ion (Zn(2+)) is tetrahedrally-coordinated by four amino acids including H271. The WalK(H271Y) mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn(2+)-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn(2+) sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon. Nature Publishing Group UK 2019-07-11 /pmc/articles/PMC6624279/ /pubmed/31296851 http://dx.doi.org/10.1038/s41467-019-10932-4 Text en © 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/.
spellingShingle Article
Monk, Ian R.
Shaikh, Nausad
Begg, Stephanie L.
Gajdiss, Mike
Sharkey, Liam K. R.
Lee, Jean Y. H.
Pidot, Sacha J.
Seemann, Torsten
Kuiper, Michael
Winnen, Brit
Hvorup, Rikki
Collins, Brett M.
Bierbaum, Gabriele
Udagedara, Saumya R.
Morey, Jacqueline R.
Pulyani, Neha
Howden, Benjamin P.
Maher, Megan J.
McDevitt, Christopher A.
King, Glenn F.
Stinear, Timothy P.
Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
title Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
title_full Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
title_fullStr Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
title_full_unstemmed Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
title_short Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
title_sort zinc-binding to the cytoplasmic pas domain regulates the essential walk histidine kinase of staphylococcus aureus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624279/
https://www.ncbi.nlm.nih.gov/pubmed/31296851
http://dx.doi.org/10.1038/s41467-019-10932-4
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