Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome.
Blood
; 125(15): 2359-69, 2015 Apr 09.
Article
en En
| MEDLINE
| ID: mdl-25608561
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Complemento C3
/
Mapas de Interacción de Proteínas
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Síndrome Hemolítico Urémico Atípico
Tipo de estudio:
Etiology_studies
/
Incidence_studies
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Observational_studies
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Prognostic_studies
/
Risk_factors_studies
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
Blood
Año:
2015
Tipo del documento:
Article