Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5916493 | Molecular Immunology | 2015 | 11 Pages |
Abstract
Atypical hemolytic uremic syndrome (aHUS) associates with complement dysregulation caused by mutations and polymorphisms in complement activators and regulators. However, the reasons why some mutations in complement proteins predispose to aHUS are poorly understood. Here, we have investigated the functional consequences of three aHUS-associated mutations in C3, R592W, R161W and I1157T. First, we provide evidence that penetrance and disease severity for these mutations is modulated by inheritance of documented “risk” haplotypes as has been observed with mutations in other complement genes. Next, we show that all three mutations markedly reduce the efficiency of factor I-mediated C3b cleavage when catalyzed by membrane cofactor protein (MCP), but not when catalyzed by factor H. Biacore analysis showed that each mutant C3b bound sMCP (recombinant soluble MCP; CD46) at reduced affinity, providing a molecular basis for its reduced cofactor activity. Lastly, we show by electron microscopy structural analysis a displacement of the TED domain from the MG ring in C3b in two of the C3 mutants that explains these defects in regulation. As a whole our data suggest that aHUS-associated mutations in C3 selectively affect regulation of complement on surfaces and provide a structural framework to predict the functional consequences of the C3 genetic variants found in patients.
Keywords
TEDCR1MCPDDDDAFaHUSdense deposit diseaseSurface plasmon resonanceSPRequilibrium dissociation constantshort consensus repeatComplement C3MutantAtypical hemolytic uremic syndromefactor DFactor BFactor Hfactor Ialternative pathwaylectin pathwayclassical pathwayMACElectron microscopywild-typemembrane cofactor proteinmembrane attack complexDecay accelerating factorcomplement receptor 1SCR
Related Topics
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Biochemistry, Genetics and Molecular Biology
Molecular Biology
Authors
Rubén MartÃnez-Barricarte, Meike Heurich, Andrés López-Perrote, Agustin Tortajada, Sheila Pinto, Margarita López-Trascasa, Pilar Sánchez-Corral, B. Paul Morgan, Oscar Llorca, Claire L. Harris, Santiago RodrÃguez de Córdoba,