Multiscale Conformational Heterogeneity in Staphylococcal Protein A: Possible Determinant of Functional Plasticity

• Published in: Structure (London) Vol. 22; no. 10; pp. 1467 - 1477
• Main Authors: Deis, Lindsay N., Pemble, Charles W., Qi, Yang, Hagarman, Andrew, Richardson, David C., Richardson, Jane S., Oas, Terrence G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 07.10.2014
• Subjects: Bacteria; Binding; Crystallography, X-Ray; Heterogeneity; Models, Molecular; Networks; Plasticity; Protein A; Protein Conformation; Protein Structure, Tertiary; Proteins; Staphylococcal Protein A - chemistry; Staphylococcal Protein A - metabolism; Staphylococcus aureus; Staphylococcus aureus - chemistry
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2014.08.014

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. [Display omitted] •Multidomain staphylococcal protein A (SpA) is flexible and binds to many proteins•Atomic-resolution electron density reveals extensive conformational heterogeneity•Backbone and side chain conformations are coupled to a pivot of helix 1 around Ile16•Helix 1 conformational changes may enable SpA to bind multiple partners Deis et al. describe crystal structures of domains of a virulence factor from S. aureus. These structures show extensive conformational heterogeneity coupled to rearrangements in tertiary structure that may explain how this important virulence factor binds to the Fc fragment of antibodies and other host proteins.