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Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO

In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and...

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Autores principales: Boyaci, Hande, Shah, Tayyab, Hurley, Amanda, Kokona, Bashkim, Li, Zhijie, Ventocilla, Christian, Jeffrey, Philip D., Semmelhack, Martin F., Fairman, Robert, Bassler, Bonnie L., Hughson, Frederick M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878744/
https://www.ncbi.nlm.nih.gov/pubmed/27219477
http://dx.doi.org/10.1371/journal.pbio.1002464
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author Boyaci, Hande
Shah, Tayyab
Hurley, Amanda
Kokona, Bashkim
Li, Zhijie
Ventocilla, Christian
Jeffrey, Philip D.
Semmelhack, Martin F.
Fairman, Robert
Bassler, Bonnie L.
Hughson, Frederick M.
author_facet Boyaci, Hande
Shah, Tayyab
Hurley, Amanda
Kokona, Bashkim
Li, Zhijie
Ventocilla, Christian
Jeffrey, Philip D.
Semmelhack, Martin F.
Fairman, Robert
Bassler, Bonnie L.
Hughson, Frederick M.
author_sort Boyaci, Hande
collection PubMed
description In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. The vibrio autoinducer molecules bind to transmembrane receptors of the two-component histidine sensor kinase family. Autoinducer binding inactivates the receptors’ kinase activities, leading to dephosphorylation and inhibition of the downstream response regulator LuxO. Here, we report the X-ray structure of LuxO in its unphosphorylated, autoinhibited state. Our structure reveals that LuxO, a bacterial enhancer-binding protein of the AAA+ ATPase superfamily, is inhibited by an unprecedented mechanism in which a linker that connects the catalytic and regulatory receiver domains occupies the ATPase active site. The conformational change that accompanies receiver domain phosphorylation likely disrupts this interaction, providing a mechanistic rationale for LuxO activation. We also determined the crystal structure of the LuxO catalytic domain bound to a broad-spectrum inhibitor. The inhibitor binds in the ATPase active site and recapitulates elements of the natural regulatory mechanism. Remarkably, a single inhibitor molecule may be capable of inhibiting an entire LuxO oligomer.
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spelling pubmed-48787442016-06-09 Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO Boyaci, Hande Shah, Tayyab Hurley, Amanda Kokona, Bashkim Li, Zhijie Ventocilla, Christian Jeffrey, Philip D. Semmelhack, Martin F. Fairman, Robert Bassler, Bonnie L. Hughson, Frederick M. PLoS Biol Research Article In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. The vibrio autoinducer molecules bind to transmembrane receptors of the two-component histidine sensor kinase family. Autoinducer binding inactivates the receptors’ kinase activities, leading to dephosphorylation and inhibition of the downstream response regulator LuxO. Here, we report the X-ray structure of LuxO in its unphosphorylated, autoinhibited state. Our structure reveals that LuxO, a bacterial enhancer-binding protein of the AAA+ ATPase superfamily, is inhibited by an unprecedented mechanism in which a linker that connects the catalytic and regulatory receiver domains occupies the ATPase active site. The conformational change that accompanies receiver domain phosphorylation likely disrupts this interaction, providing a mechanistic rationale for LuxO activation. We also determined the crystal structure of the LuxO catalytic domain bound to a broad-spectrum inhibitor. The inhibitor binds in the ATPase active site and recapitulates elements of the natural regulatory mechanism. Remarkably, a single inhibitor molecule may be capable of inhibiting an entire LuxO oligomer. Public Library of Science 2016-05-24 /pmc/articles/PMC4878744/ /pubmed/27219477 http://dx.doi.org/10.1371/journal.pbio.1002464 Text en © 2016 Boyaci et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Boyaci, Hande
Shah, Tayyab
Hurley, Amanda
Kokona, Bashkim
Li, Zhijie
Ventocilla, Christian
Jeffrey, Philip D.
Semmelhack, Martin F.
Fairman, Robert
Bassler, Bonnie L.
Hughson, Frederick M.
Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO
title Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO
title_full Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO
title_fullStr Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO
title_full_unstemmed Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO
title_short Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO
title_sort structure, regulation, and inhibition of the quorum-sensing signal integrator luxo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878744/
https://www.ncbi.nlm.nih.gov/pubmed/27219477
http://dx.doi.org/10.1371/journal.pbio.1002464
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