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

Martínez-Barricarte, Rubén, Heurich-Sevcenco, Meike ORCID: https://orcid.org/0000-0003-0105-2702, López-Perrote, Andrés, Tortajada, Agustin, Pinto, Sheila, López-Trascasa, Margarita, Sánchez-Corral, Pilar, Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676, Llorca, Oscar, Harris, Claire L. and Rodríguez de Córdoba, Santiago 2015. The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome. Molecular Immunology 66 (2) , pp. 263-273. 10.1016/j.molimm.2015.03.248

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Abstract

Atypical hemolytic uremic syndrome (aHUS) associates with complement dysregulation caused by muta-tions and polymorphisms in complement activators and regulators. However, the reasons why somemutations in complement proteins predispose to aHUS are poorly understood. Here, we have investigatedthe 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 inheri-tance 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 cleavagewhen catalyzed by membrane cofactor protein (MCP), but not when catalyzed by factor H. Biacore anal-ysis 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 microscopystructural analysis a displacement of the TED domain from the MG ring in C3b in two of the C3 mutantsthat explains these defects in regulation. As a whole our data suggest that aHUS-associated mutations inC3 selectively affect regulation of complement on surfaces and provide a structural framework to predictthe functional consequences of the C3 genetic variants found in patients.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Additional Information:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license
Publisher:	Elsevier
ISSN:	0161-5890
Funders:	MRC
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	24 March 2015
Last Modified:	07 May 2023 19:29
URI:	https://orca.cardiff.ac.uk/id/eprint/72301

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