title: A molecular insight into complement evasion by the staphylococcal complement inhibitor protein family.
abstract: Staphylococcus aureus possesses an impressive arsenal of complement evasion proteins that help the bacterium escape attack of the immune system. The staphylococcal complement inhibitor (SCIN) protein exhibits a particularly high potency and was previously shown to block complement by acting at the level of the C3 convertases. However, many details about the exact binding and inhibitory mechanism remained unclear. In this study, we demonstrate that SCIN directly binds with nanomolar affinity to a functionally important area of C3b that lies near the C terminus of its beta-chain. Direct competition of SCIN with factor B for C3b slightly decreased the formation of surface-bound convertase. However, the main inhibitory effect can be attributed to an entrapment of the assembled convertase in an inactive state. Whereas native C3 is still able to bind to the blocked convertase, no generation and deposition of C3b could be detected in the presence of SCIN. Furthermore, SCIN strongly competes with the binding of factor H to C3b and influences its regulatory activities: the SCIN-stabilized convertase was essentially insensitive to decay acceleration by factor H and the factor I- and H-mediated conversion of surface-bound C3b to iC3b was significantly reduced. By targeting a key area on C3b, SCIN is able to block several essential functions within the alternative pathway, which explains the high potency of the inhibitor. Our findings provide an important insight into complement evasion strategies by S. aureus and may act as a base for further functional studies.
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.forename: Apostolia
authors.initials: A
authors.lastname: Tzekou
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Garcia
authors.forename: Michal
authors.initials: M
authors.lastname: Hammel
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: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Herbert
authors.forename: Paul N
authors.initials: PN
authors.lastname: Barlow
authors.forename: Brian V
authors.initials: BV
authors.lastname: Geisbrecht
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
mesh_terms: D051561:Complement C3 Convertase, Alternative Pathway / Q000378:metabolism / Q000502:physiology; D003179:Complement C3b / Q000737:chemistry / Q000378:metabolism*; D011415:Complement Factor B / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D005810:Multigene Family / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity; D014774:Virulence
chemical_list: D003169:Complement Inactivator Proteins; D003179:Complement C3b; D017242:Complement Factor H; D051561:Complement C3 Convertase, Alternative Pathway; D011415:Complement Factor B