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Structural and functional analysis of RopB: a major virulence regulator in S treptococcus pyogenes
Group A Streptococcus (GAS) is an exclusive human pathogen that causes significant disease burden. Global regulator RopB of GAS controls the expression of several major virulence factors including secreted protease SpeB during high cell density. However, the molecular mechanism for RopB‐dependent sp...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794775/ https://www.ncbi.nlm.nih.gov/pubmed/26714274 http://dx.doi.org/10.1111/mmi.13294 |
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author | Makthal, Nishanth Gavagan, Maire Do, Hackwon Olsen, Randall J. Musser, James M. Kumaraswami, Muthiah |
author_facet | Makthal, Nishanth Gavagan, Maire Do, Hackwon Olsen, Randall J. Musser, James M. Kumaraswami, Muthiah |
author_sort | Makthal, Nishanth |
collection | PubMed |
description | Group A Streptococcus (GAS) is an exclusive human pathogen that causes significant disease burden. Global regulator RopB of GAS controls the expression of several major virulence factors including secreted protease SpeB during high cell density. However, the molecular mechanism for RopB‐dependent speB expression remains unclear. To understand the mechanism of transcription activation by RopB, we determined the crystal structure of the C‐terminal domain of RopB. RopB‐CTD has the TPR motif, a signature motif involved in protein–peptide interactions and shares significant structural homology with the quorum sensing RRNPP family regulators. Characterization of the high cell density‐specific cell‐free growth medium demonstrated the presence of a low molecular weight proteinaceous secreted factor that upregulates RopB‐dependent speB expression. Together, these results suggest that RopB and its cognate peptide signals constitute an intercellular signalling machinery that controls the virulence gene expression in concert with population density. Structure‐guided mutational analyses of RopB dimer interface demonstrated that single alanine substitutions at this critical interface significantly altered RopB‐dependent speB expression and attenuated GAS virulence. Results presented here suggested that a properly aligned RopB dimer interface is important for GAS pathogenesis and highlighted the dimerization interactions as a plausible therapeutic target for the development of novel antimicrobials. |
format | Online Article Text |
id | pubmed-4794775 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-47947752016-03-21 Structural and functional analysis of RopB: a major virulence regulator in S treptococcus pyogenes Makthal, Nishanth Gavagan, Maire Do, Hackwon Olsen, Randall J. Musser, James M. Kumaraswami, Muthiah Mol Microbiol Research Articles Group A Streptococcus (GAS) is an exclusive human pathogen that causes significant disease burden. Global regulator RopB of GAS controls the expression of several major virulence factors including secreted protease SpeB during high cell density. However, the molecular mechanism for RopB‐dependent speB expression remains unclear. To understand the mechanism of transcription activation by RopB, we determined the crystal structure of the C‐terminal domain of RopB. RopB‐CTD has the TPR motif, a signature motif involved in protein–peptide interactions and shares significant structural homology with the quorum sensing RRNPP family regulators. Characterization of the high cell density‐specific cell‐free growth medium demonstrated the presence of a low molecular weight proteinaceous secreted factor that upregulates RopB‐dependent speB expression. Together, these results suggest that RopB and its cognate peptide signals constitute an intercellular signalling machinery that controls the virulence gene expression in concert with population density. Structure‐guided mutational analyses of RopB dimer interface demonstrated that single alanine substitutions at this critical interface significantly altered RopB‐dependent speB expression and attenuated GAS virulence. Results presented here suggested that a properly aligned RopB dimer interface is important for GAS pathogenesis and highlighted the dimerization interactions as a plausible therapeutic target for the development of novel antimicrobials. John Wiley and Sons Inc. 2016-02-19 2016-03 /pmc/articles/PMC4794775/ /pubmed/26714274 http://dx.doi.org/10.1111/mmi.13294 Text en © 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Makthal, Nishanth Gavagan, Maire Do, Hackwon Olsen, Randall J. Musser, James M. Kumaraswami, Muthiah Structural and functional analysis of RopB: a major virulence regulator in S treptococcus pyogenes |
title | Structural and functional analysis of RopB: a major virulence regulator in S
treptococcus pyogenes
|
title_full | Structural and functional analysis of RopB: a major virulence regulator in S
treptococcus pyogenes
|
title_fullStr | Structural and functional analysis of RopB: a major virulence regulator in S
treptococcus pyogenes
|
title_full_unstemmed | Structural and functional analysis of RopB: a major virulence regulator in S
treptococcus pyogenes
|
title_short | Structural and functional analysis of RopB: a major virulence regulator in S
treptococcus pyogenes
|
title_sort | structural and functional analysis of ropb: a major virulence regulator in s
treptococcus pyogenes |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794775/ https://www.ncbi.nlm.nih.gov/pubmed/26714274 http://dx.doi.org/10.1111/mmi.13294 |
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