Multiscale conformational heterogeneity in staphylococcal protein a: possible determinant of functional plasticity.
Date
2014-10-07
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Abstract
The Staphylococcus aureus virulence factor staphylococcal protein A (SpA) is a major contributor to bacterial evasion of the host immune system, through high-affinity binding to host proteins such as antibodies. SpA includes five small three-helix-bundle domains (E-D-A-B-C) separated by conserved flexible linkers. Prior attempts to crystallize individual domains in the absence of a binding partner have apparently been unsuccessful. There have also been no previous structures of tandem domains. Here we report the high-resolution crystal structures of a single C domain, and of two B domains connected by the conserved linker. Both structures exhibit extensive multiscale conformational heterogeneity, which required novel modeling protocols. Comparison of domain structures shows that helix1 orientation is especially heterogeneous, coordinated with changes in side chain conformational networks and contacting protein interfaces. This represents the kind of structural plasticity that could enable SpA to bind multiple partners.
Type
Department
Description
Provenance
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Deis, Lindsay N, Charles W Pemble, Yang Qi, Andrew Hagarman, David C Richardson, Jane S Richardson and Terrence G Oas (2014). Multiscale conformational heterogeneity in staphylococcal protein a: possible determinant of functional plasticity. Structure, 22(10). pp. 1467–1477. 10.1016/j.str.2014.08.014 Retrieved from https://hdl.handle.net/10161/11167.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
David C. Richardson
Protein structure, folding, and design; 3D computer graphics; x-ray crystallography.
Jane Shelby Richardson
3D structure of macromolecules; molecular graphics; protein folding and design; all-atom contacts; x-ray crystallography; structure validation.
Terrence Gilbert Oas
Our laboratory is primarily interested in the mechanisms of protein folding. We use nuclear magnetic resonance (NMR) and other types of spectroscopy to study the solution structure, stability and folding reactions of small protein models. These include monomeric λ repressor, the B domain of protein A (BdpA) and various regulator of G-protein signalling (RGS) domains. Our biophysical studies are used to inform our investigations of the role of folding mechanism in the function of proteins in the cell. For example, a naturally occuring cancer-causing mutation in the RGS domain of axin appears to lower the thermodynamic stability of the domain. We are developing methods to compensate for such destabilizing mutations, thereby restoring normal function to the protein.We are also developing computational models of protein folding as a way to better understand the mechanisms and as a tool in the design of new experiments.
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.