Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure.

2.50
Hdl Handle:
http://hdl.handle.net/10541/72696
Title:
Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure.
Authors:
Herbert, A; Uhrín, D; Lyon, Malcolm; Pangburn, M; Barlow, P
Abstract:
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.
Affiliation:
Edinburgh Biomolecular NMR Unit, University of Edinburgh, West mains Road, Edinburgh EH9 3JJ, United Kingdom.
Citation:
Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure. 2006, 281 (24):16512-20 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
16-Jun-2006
URI:
http://hdl.handle.net/10541/72696
DOI:
10.1074/jbc.M513611200
PubMed ID:
16533809
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorHerbert, A-
dc.contributor.authorUhrín, D-
dc.contributor.authorLyon, Malcolm-
dc.contributor.authorPangburn, M-
dc.contributor.authorBarlow, P-
dc.date.accessioned2009-07-07T09:45:05Z-
dc.date.available2009-07-07T09:45:05Z-
dc.date.issued2006-06-16-
dc.identifier.citationDisease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure. 2006, 281 (24):16512-20 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid16533809-
dc.identifier.doi10.1074/jbc.M513611200-
dc.identifier.urihttp://hdl.handle.net/10541/72696-
dc.description.abstractMutations 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.en
dc.language.isoenen
dc.subject.meshAmino Acid Sequence-
dc.subject.meshAnions-
dc.subject.meshComplement C3d-
dc.subject.meshComplement Factor H-
dc.subject.meshHeparin-
dc.subject.meshHumans-
dc.subject.meshMagnetic Resonance Spectroscopy-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshPichia-
dc.subject.meshPolymorphism, Genetic-
dc.subject.meshProtein Conformation-
dc.subject.meshSaccharomyces cerevisiae-
dc.subject.meshSequence Homology, Amino Acid-
dc.titleDisease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure.en
dc.typeArticleen
dc.contributor.departmentEdinburgh Biomolecular NMR Unit, University of Edinburgh, West mains Road, Edinburgh EH9 3JJ, United Kingdom.en
dc.identifier.journalThe Journal of Biological Chemistryen

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