2bzm

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SOLUTION STRUCTURE OF THE PRIMARY HOST RECOGNITION REGION OF COMPLEMENT FACTOR H

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Mutations and polymorphisms in the regulator of complement activation, factor H, have been linked to atypical hemolytic uremic syndrome (aHUS), membranoproliferative glomerulonephritis, and age-related macular, degeneration. Many aHUS patients carry mutations in the two C-terminal, modules of factor H, which normally confer upon this abundant 155-kDa, plasma glycoprotein its ability to selectively bind self-surfaces and, prevent them from inappropriately triggering the complement cascade via, the alternative pathway. In the current study, the three-dimensional, solution structure of the C-terminal module pair of factor H has been, determined. A binding site for a fully sulfated heparin-derived, tetrasaccharide has been delineated using chemical shift mapping and the, C3d/C3b-binding site inferred from sequence comparisons and computational, docking. The resultant information allows assessment of the likely, consequences of aHUS-associated amino acid substitutions in this critical, region of factor H. It is striking that, excepting those likely to perturb, the three-dimensional structure, aHUS-associated missense mutations, congregate in the polyanion-binding site delineated in this study, thus, potentially disrupting a vital mechanism for control of complement on, self-surfaces in the microvasculature of the kidney. It is intriguing that, a single nucleotide polymorphism predisposing to age-related macular, degeneration occupies another region of factor H that harbors a, polyanion-binding site.

Disease

Known diseases associated with this structure: Complement factor H deficiency OMIM:[134370], Factor H and factor H-like 1 OMIM:[134370], Hemolytic-uremic syndrome OMIM:[134370], Macular degeneration, age-related, 4 OMIM:[134370], Membranoproliferative glomerulonephritis with CFH deficiency OMIM:[134370]

About this Structure

2BZM is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure., Herbert AP, Uhrin D, Lyon M, Pangburn MK, Barlow PN, J Biol Chem. 2006 Jun 16;281(24):16512-20. Epub 2006 Mar 13. PMID:16533809

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