4.5 Article

The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome

Journal

MOLECULAR IMMUNOLOGY
Volume 66, Issue 2, Pages 263-273

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2015.03.248

Keywords

Complement C3; C3 mutation; MCP; Factor H; TED; Atypical hemolytic uremic syndrome

Funding

  1. Spanish Ministerio de Economia y Competitividad [SAF2011-26583, PI12-00597, SAF2011-22988]
  2. Fundacion Renal Inigo Alvarez de Toledo
  3. Seventh Framework Program European Union Project EURenOmics [305608]
  4. Autonomous Region of Madrid [S2010/BMD-2316]
  5. Medical Research Council, United Kingdom [G0701298]
  6. MRC [G0701298] Funding Source: UKRI
  7. Medical Research Council [G0701298] Funding Source: researchfish

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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 0 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. (C) 2015 The Authors. Published by Elsevier Ltd.

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