title: Allosteric inhibition of complement function by a staphylococcal immune evasion protein.
abstract: The complement system is a major target of immune evasion by Staphylococcus aureus. Although many evasion proteins have been described, little is known about their molecular mechanisms of action. Here we demonstrate that the extracellular fibrinogen-binding protein (Efb) from S. aureus acts as an allosteric inhibitor by inducing conformational changes in complement fragment C3b that propagate across several domains and influence functional regions far distant from the Efb binding site. Most notably, the inhibitor impaired the interaction of C3b with complement factor B and, consequently, formation of the active C3 convertase. As this enzyme complex is critical for both activation and amplification of the complement response, its allosteric inhibition likely represents a fundamental contribution to the overall immune evasion strategy of S. aureus.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.forename: Michal
authors.initials: M
authors.lastname: Hammel
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Garcia
authors.forename: William J
authors.initials: WJ
authors.lastname: McWhorter
authors.forename: Georgia
authors.initials: G
authors.lastname: Sfyroera
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Wu
authors.forename: Apostolia
authors.initials: A
authors.lastname: Tzekou
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Brian V
authors.initials: BV
authors.lastname: Geisbrecht
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Woods
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D003179:Complement C3b / Q000737:chemistry / Q000378:metabolism*; D011415:Complement Factor B / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000737:chemistry / Q000378:metabolism*; D057131:Immune Evasion / Q000502:physiology*; D013058:Mass Spectrometry; D008958:Models, Molecular; D011487:Protein Conformation; D053838:Scattering, Small Angle; D013211:Staphylococcus aureus / Q000378:metabolism / Q000502:physiology*; D020349:Surface Plasmon Resonance
chemical_list: D001426:Bacterial Proteins; D003169:Complement Inactivator Proteins; C524396:Ehp protein, Staphylococcus aureus; D003179:Complement C3b; D050577:Complement C3-C5 Convertases; D011415:Complement Factor B