Document Detail


Implications of the progressive self-association of wild-type human factor H for complement regulation and disease.
MedLine Citation:
PMID:  18054958     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Factor H (FH) is a major regulator of complement alternative pathway activation. It is composed of 20 short complement regulator (SCR) domains and is genetically associated as a risk factor for age-related macular degeneration. Previous studies on FH suggested that it existed in monomeric and dimeric forms. Improved X-ray scattering and analytical ultracentrifugation methodology for wild-type FH permitted a clarification of these oligomeric properties. Data at lower concentrations revealed a dependence of the X-ray radius of gyration values on concentration that corresponded to the weak self-association of FH. Global sedimentation equilibrium fits indicated that a monomer-dimer equilibrium best described the data up to 1.3 mg/ml with a fitted dissociation constant K(D) of 28 microM and that higher oligomers formed at increased concentrations. The K(D) showed that about 85-95% of serum FH will be monomeric in the absence of other factors. Size-distribution analyses in sedimentation velocity experiments showed that monomeric FH was the major species but that as many as six oligomeric forms co-existed with it. The data were explained in terms of two weak dimerisation sites recently identified in the SCR-6/8 and SCR-16/20 fragments of FH with similar K(D) values. These observations indicate a mechanism for the progressive self-association of FH and may be relevant for complement regulation and the formation of drusen deposits that are associated with age-related macular degeneration.
Authors:
Ruodan Nan; Jayesh Gor; Stephen J Perkins
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-11-13
Journal Detail:
Title:  Journal of molecular biology     Volume:  375     ISSN:  1089-8638     ISO Abbreviation:  J. Mol. Biol.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2008-01-01     Completed Date:  2008-01-29     Revised Date:  2014-10-14    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  891-900     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Amino Acid Substitution
Binding Sites
Complement Factor H / chemistry*,  genetics*,  isolation & purification,  metabolism*
Dimerization
Gene Expression Regulation*
Hemolytic-Uremic Syndrome / etiology,  pathology
Histidine / metabolism
Humans
Models, Molecular
Molecular Sequence Data
Molecular Weight
Optic Disk Drusen / etiology,  pathology
Polymorphism, Genetic
Protein Binding
Protein Structure, Tertiary
Scattering, Radiation
Synchrotrons
Ultracentrifugation
X-Rays
Grant Support
ID/Acronym/Agency:
BB/E013104/1//Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
4QD397987E/Histidine; 80295-65-4/Complement Factor H

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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