title: Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode.
abstract: Regulators of complement activation (RCA) inhibit complement-induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i-iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b-binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease-related mutations and immune evasion.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
authors.forename: Federico
authors.identifier: 0000-0002-7818-1804
authors.initials: F
authors.lastname: Forneris
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel
authors.identifier: 0000-0001-6140-0233
authors.initials: D
authors.lastname: Ricklin
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Zhuoer
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Sfyroera
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Apostolia
authors.initials: A
authors.lastname: Tzekou
authors.affiliation: Department of Pediatric Nephrology (830), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Elena
authors.initials: E
authors.lastname: Volokhina
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
authors.forename: Joke Cm
authors.initials: JC
authors.lastname: Granneman
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hauhart
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Bertram
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: M Kathryn
authors.initials: MK
authors.lastname: Liszewski
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands p.gros@uu.nl.
authors.forename: Piet
authors.identifier: 0000-0002-7782-2585
authors.initials: P
authors.lastname: Gros
mesh_terms: D001665:Binding Sites; D018958:CD55 Antigens / Q000737:chemistry / Q000378:metabolism; D003167:Complement Activation; D003179:Complement C3b / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000737:chemistry / Q000378:metabolism; D000072417:Protein Domains; D017463:Receptors, Complement 3b / Q000737:chemistry / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C497857:CD46 protein, human; D018958:CD55 Antigens; C509991:CR1 protein, human; D051916:Membrane Cofactor Protein; D017463:Receptors, Complement 3b; C532808:SPICE protein, variola virus; D014763:Viral Matrix Proteins; D003179:Complement C3b
keywords: cofactor activity; complement; decay‐accelerating activity; immune evasion; regulators of complement activity