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Factor H and Atypical Hemolytic Uremic Syndrome: Mutations in the C-Terminus Cause Structural Changes and Defective Recognition Functions

Mihály Józsi^*, Stefan Heinen^*, Andrea Hartmann^*, Clemens W. Ostrowicz^*, Steffi Hälbich^*, Heiko Richter^*, Anja Kunert^*, Christoph Licht, Rebecca E. Saunders, Stephen J. Perkins, Peter F. Zipfel^*, and Christine Skerka^*

^* Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany; Children’s Hospital of the University of Cologne, Pediatric Nephrology, Cologne, Germany; Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College London, London, United Kingdom; and Frierich Schiller University, Jena, Germany

Address correspondence to: Dr. Christine Skerka, Department of Infection Biology, Leibniz Institute for Natural Product Research, and Infection Biology, Beutenbergstrasse 11a, 07745 Jena, Germany. Phone: +49-3641-656848; Fax: +49-3641-656902; E-mail: christine.skerka{at}hki-jena.de

Received for publication August 19, 2005. Accepted for publication October 15, 2005.

Atypical hemolytic uremic syndrome is a disease that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations in the complement regulator factor H are associated with the inherited form of the disease, and >60% of the mutations are located within the C terminus of factor H. The C-terminus of factor H, represented by short consensus repeat 19 (SCR19) and SCR20, harbors multiple functions; consequently, this study aimed to examine the functional effects of clinically reported mutations in these SCR. Mutant factor H proteins (W1157R, W1183L, V1197A, R1210C, R1215G, and P1226S) were recombinantly expressed and functionally characterized. All six mutant proteins showed severely reduced heparin, C3b, C3d, and endothelial cell binding. By peptide spot analyses, four linear regions that are involved in heparin, C3b, and C3d binding were localized in SCR19 and SCR20. A three-dimensional homology model of the two domains suggests that these four regions form a common binding site across both domains. In addition, this structural model identifies two types of residues: Type A residues are positioned on the SCR surface and are represented by mutants W1157R, W1183L, R1210C, and R1215G; and type B residues are buried within the SCR structure and affect mutations V1197A and P1226S. Mutations of both types of residue result in the same functional defects, namely the reduced binding of factor H to surface-attached C3b molecules and reduced complement regulatory activity at the cell surfaces. The buried type B mutations seem to affect ligand interaction of factor H more severely than the surface-exposed mutations.

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