Title | Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Boyaci, H, Shah, T, Hurley, A, Kokona, B, Li, Z, Ventocilla, C, Jeffrey, PD, Semmelhack, MF, Fairman, R, Bassler, BL, Hughson, FM |
Journal | PLoS Biol |
Volume | 14 |
Issue | 5 |
Pagination | e1002464 |
Date Published | 2016 May |
ISSN | 1545-7885 |
Keywords | Bacterial Proteins, Binding Sites, Crystallography, X-Ray, Models, Molecular, Phosphorylation, Protein Domains, Repressor Proteins, Uracil |
Abstract | <p>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.</p> |
DOI | 10.1371/journal.pbio.1002464 |
Alternate Journal | PLoS Biol |
PubMed ID | 27219477 |
PubMed Central ID | PMC4878744 |
Grant List | R01 GM065859 / GM / NIGMS NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States P41 GM111244 / GM / NIGMS NIH HHS / United States R37 GM065859 / GM / NIGMS NIH HHS / United States R01 AI054442 / AI / NIAID NIH HHS / United States P41 GM103485 / GM / NIGMS NIH HHS / United States R56 AI091681 / AI / NIAID NIH HHS / United States P30 EB009998 / EB / NIBIB NIH HHS / United States |