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Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode.
Forneris, Federico; Wu, Jin; Xue, Xiaoguang; Ricklin, Daniel; Lin, Zhuoer; Sfyroera, Georgia; Tzekou, Apostolia; Volokhina, Elena; Granneman, Joke Cm; Hauhart, Richard; Bertram, Paula; Liszewski, M Kathryn; Atkinson, John P; Lambris, John D; Gros, Piet.
Afiliación
  • Forneris F; Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
  • Wu J; Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
  • Xue X; Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
  • Ricklin D; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Lin Z; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Sfyroera G; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Tzekou A; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Volokhina E; Department of Pediatric Nephrology (830), Radboud University Medical Center, Nijmegen, The Netherlands.
  • Granneman JC; Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands.
  • Hauhart R; Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
  • Bertram P; Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
  • Liszewski MK; Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
  • Atkinson JP; Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
  • Lambris JD; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Gros P; Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science Utrecht University, Utrecht, The Netherlands p.gros@uu.nl.
EMBO J ; 35(10): 1133-49, 2016 05 17.
Article en En | MEDLINE | ID: mdl-27013439
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C3b Límite: Humans Idioma: En Revista: EMBO J Año: 2016 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C3b Límite: Humans Idioma: En Revista: EMBO J Año: 2016 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido