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Lookup NU author(s): Professor David KavanaghORCiD
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The soluble 155 kDa glycoprotein factor H (FH) protects host tissue from damage by the human complement system. It accelerates decay of the alternative-pathway C3 convertase, C3bBb, and is a cofactor for factor I-mediated cleavage of the opsonin C3b. Numerous mutations and single-nucleotide polymorphisms (SNPs) occur in the gene encoding FH and the resulting missense mutations and truncation products result in altered functionality that predisposes to the development of the serious renal condition atypical haemolytic uraemic syndrome (aHUS). Other polymorphisms are linked to membranoproliferative glomerulonephritis and macular degeneration. The two C-terminal modules of FH (FH19-20) harbour numerous aHUS-associated mutations that disrupt the ability of factor H to protect host cells from complement-mediated damage. In this work, the crystal structure of an aHUS-associated T1184R variant of FH19-20 at a resolution of 1.52 angstrom is described. It is shown that this mutation has negligible structural effects but causes a significant change in the electrostatic surface of these two domains. Mechanisms are discussed by which this mutation may alter FH-ligand interactions, particularly with regard to the extension of a region of this molecule within module 20 that has been associated with the binding of glycosaminoglycans (GAGs) or sialic acid residues.
Author(s): Morgan HP, Jiang JZ, Herbert AP, Kavanagh D, Uhrin D, Barlow PN, Hannan JP
Publication type: Article
Publication status: Published
Journal: Acta Crystallographica Section D: Biological Crystallography
Year: 2011
Volume: 67
Pages: 593-600
Print publication date: 01/07/2011
ISSN (print): 0907-4449
ISSN (electronic): 1399-0047
Publisher: Wiley-Blackwell
URL: http://dx.doi.org/10.1107/S0907444911015423
DOI: 10.1107/S0907444911015423
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