Suppression of conformational heterogeneity at a protein-protein interface.
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Staphylococcal protein A (SpA) is an important virulence factor from Staphylococcus aureus responsible 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. Suppression of conformational heterogeneity may be an important structural paradigm in functionally plastic proteins.
SubjectStaphylococcus aureus virulence
immunoglobulin Fc binding
staphylococcal protein A
Amino Acid Sequence
Immunoglobulin Fc Fragments
Magnetic Resonance Spectroscopy
Molecular Sequence Data
Protein Structure, Secondary
Staphylococcal Protein A
Structural Homology, Protein
Published Version (Please cite this version)10.1073/pnas.1424724112
Publication InfoDaniels, Kyle G; Deis, LN; Oas, Terrence Gilbert; Qi, Y; Wang, Y; Wu, Q; & Zhou, Pei (2015). Suppression of conformational heterogeneity at a protein-protein interface. Proc Natl Acad Sci U S A, 112(29). pp. 9028-9033. 10.1073/pnas.1424724112. Retrieved from https://hdl.handle.net/10161/10595.
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Professor of Biochemistry
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 pro
Professor of Biochemistry
Protein-protein interactions play a pivotal role in the regulation of various cellular processes. The formation of higher order protein complexes is frequently accompanied by extensive structural remodeling of the individual components, varying from domain re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for macromolecular structure determination in solution. It has the unique advantage of being capable of elucidati
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