Toggle Main Menu Toggle Search

Open Access padlockePrints

Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome

Lookup NU author(s): Dr Valerie Wilson, Professor Tim Goodship, Dr Veronique Fremaux-Bacchi

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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.


Publication metadata

Author(s): Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P, Hue C, Maga T, Valoti E, Wilson V, Jokiranta S, Smith RJH, Noris M, Goodship T, Atkinson JP, Fremeaux-Bacchi V

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2015

Volume: 125

Issue: 15

Pages: 2359-2369

Print publication date: 09/04/2015

Online publication date: 21/01/2015

Acceptance date: 07/01/2015

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: http://dx.doi.org/10.1182/blood-2014-10-609073

DOI: 10.1182/blood-2014-10-609073


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share