Suppression of conformational heterogeneity at a protein–protein interface
Abstract
Staphylococcal protein A (SpA) is an important virulence factor fromStaphylococcus aureusresponsible for the bacterium’s evasion of the host immune system. SpA includes five small three-helix–bundle domains that can each bind with high affinity to many host proteins such as antibodies. The interaction between a SpA domain and the Fc fragment of IgG was partially elucidated previously in the crystal structure 1FC2. Although informative, the previous structure was not properly folded and left many substantial questions unanswered, such as a detailed description of the tertiary structure of SpA domains in complex with Fc and the structural changes that take place upon binding. Here we report the 2.3-Å structure of a fully folded SpA domain in complex with Fc. Our structure indicates that there are extensive structural rearrangements necessary for binding Fc, including a general reduction in SpA conformational heterogeneity, freezing out of polyrotameric interfacial residues, and displacement of a SpA side chain by an Fc side chain in a molecular-recognition pocket. Such a loss of conformational heterogeneity upon formation of the protein–protein interface may occur when SpA binds its multiple binding partners. As a result, suppression of conformational heterogeneity may be an important structural paradigm in functionally plastic proteins.
- Authors:
-
- Duke Univ., Durham, NC (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1239417
- Grant/Contract Number:
- W-31-109-Eng-38; R01-GM081666
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 112; Journal Issue: 29; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Staphylococcus aureus virulence; conformational heterogeneity; staphylococcal protein A; X-ray; crystallography; immunoglobulin Fc binding
Citation Formats
Deis, Lindsay N., Wu, Qinglin, Wang, You, Qi, Yang, Daniels, Kyle G., Zhou, Pei, and Oas, Terrence G. Suppression of conformational heterogeneity at a protein–protein interface. United States: N. p., 2015.
Web. doi:10.1073/pnas.1424724112.
Deis, Lindsay N., Wu, Qinglin, Wang, You, Qi, Yang, Daniels, Kyle G., Zhou, Pei, & Oas, Terrence G. Suppression of conformational heterogeneity at a protein–protein interface. United States. https://doi.org/10.1073/pnas.1424724112
Deis, Lindsay N., Wu, Qinglin, Wang, You, Qi, Yang, Daniels, Kyle G., Zhou, Pei, and Oas, Terrence G. Wed .
"Suppression of conformational heterogeneity at a protein–protein interface". United States. https://doi.org/10.1073/pnas.1424724112. https://www.osti.gov/servlets/purl/1239417.
@article{osti_1239417,
title = {Suppression of conformational heterogeneity at a protein–protein interface},
author = {Deis, Lindsay N. and Wu, Qinglin and Wang, You and Qi, Yang and Daniels, Kyle G. and Zhou, Pei and Oas, Terrence G.},
abstractNote = {Staphylococcal protein A (SpA) is an important virulence factor fromStaphylococcus aureusresponsible for the bacterium’s evasion of the host immune system. SpA includes five small three-helix–bundle domains that can each bind with high affinity to many host proteins such as antibodies. The interaction between a SpA domain and the Fc fragment of IgG was partially elucidated previously in the crystal structure 1FC2. Although informative, the previous structure was not properly folded and left many substantial questions unanswered, such as a detailed description of the tertiary structure of SpA domains in complex with Fc and the structural changes that take place upon binding. Here we report the 2.3-Å structure of a fully folded SpA domain in complex with Fc. Our structure indicates that there are extensive structural rearrangements necessary for binding Fc, including a general reduction in SpA conformational heterogeneity, freezing out of polyrotameric interfacial residues, and displacement of a SpA side chain by an Fc side chain in a molecular-recognition pocket. Such a loss of conformational heterogeneity upon formation of the protein–protein interface may occur when SpA binds its multiple binding partners. As a result, suppression of conformational heterogeneity may be an important structural paradigm in functionally plastic proteins.},
doi = {10.1073/pnas.1424724112},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 29,
volume = 112,
place = {United States},
year = {Wed Jul 08 00:00:00 EDT 2015},
month = {Wed Jul 08 00:00:00 EDT 2015}
}
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