title: Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome.
abstract: The pathogenesis of atypical hemolytic uremic syndrome (aHUS) is strongly linked to dysregulation of the alternative pathway of the complement system. Mutations in complement genes have been identified in about two-thirds of cases, with 5% to 15% being in C3. In this study, 23 aHUS-associated genetic changes in C3 were characterized relative to their interaction with the control proteins factor H (FH), membrane cofactor protein (MCP; CD46), and complement receptor 1 (CR1; CD35). In surface plasmon resonance experiments, 17 mutant recombinant proteins demonstrated a defect in binding to FH and/or MCP, whereas 2 demonstrated reduced binding to CR1. In the majority of cases, decreased binding affinity translated to a decrease in proteolytic inactivation (known as cofactor activity) of C3b via FH and MCP. These results were used to map the putative binding regions of C3b involved in the interaction with MCP and CR1 and interrogated relative to known FH binding sites. Seventy-six percent of patients with C3 mutations had low C3 levels that correlated with disease severity. This study expands our knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction of C3 with complement regulatory proteins mediating cofactor activity.
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO;
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Schramm
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, France;
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, France;
authors.forename: Tania
authors.initials: T
authors.lastname: Rybkine
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Chauvet
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris, France;
authors.forename: Paula
authors.initials: P
authors.lastname: Vieira-Martins
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, and Rare Renal Disease Clinic, Departments of Pediatrics and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA;
authors.forename: Tara
authors.initials: T
authors.lastname: Maga
authors.affiliation: Laboratory of Immunology and Genetics of Transplantation and Rare Diseases, Mario Negri Institute for Pharmacological Research, Ranica Bergamo, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Valoti
authors.affiliation: Northern Molecular Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom;
authors.forename: Valerie
authors.initials: V
authors.lastname: Wilson
authors.affiliation: Department of Bacteriology and Immunology, Medicum, and Research Programs Unit, Immunobiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;
authors.forename: Sakari
authors.initials: S
authors.lastname: Jokiranta
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, and Rare Renal Disease Clinic, Departments of Pediatrics and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA;
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Laboratory of Immunology and Genetics of Transplantation and Rare Diseases, Mario Negri Institute for Pharmacological Research, Ranica Bergamo, Italy;
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; and.
authors.forename: Tim
authors.initials: T
authors.lastname: Goodship
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO;
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites; D015331:Cohort Studies; D003176:Complement C3 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D060066:Protein Interaction Maps
chemical_list: D003176:Complement C3