Document Detail

Biophysical characterisation of fibulin-5 proteins associated with disease.
MedLine Citation:
PMID:  20599547     Owner:  NLM     Status:  MEDLINE    
FBLN5 encodes fibulin-5, an extracellular matrix calcium-binding glycoprotein that is essential for elastic fibre formation. FBLN5 mutations are associated with two distinct human diseases, age-related macular degeneration (AMD) and cutis laxa (CL), but the biochemical basis for the pathogenic effects of these mutations is poorly understood. Two missense mutations found in AMD patients (I169T and G267S) and two missense mutations found in CL patients (G202R and S227P) were analysed in a native-like context in recombinant fibulin-5 fragments. Limited proteolysis, NMR spectroscopy and chromophoric calcium chelation experiments showed that the G267S and S227P substitutions cause long-range structural effects consistent with protein misfolding. Cellular studies using fibroblast cells further demonstrated that these recombinant forms of mutant fibulin-5 were not present in the extracellular medium, consistent with retention. In contrast, no significant effects of I169T and G202R substitutions on protein fold and secretion were identified. These data establish protein misfolding as a causative basis for the effects of G267S and S227P substitutions in AMD and CL, respectively, and raise the possibility that the I169T and G202R substitutions may be polymorphisms or may increase susceptibility to disease.
Ralf Schneider; Sacha A Jensen; Pat Whiteman; James S O McCullagh; Christina Redfield; Penny A Handford
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-25
Journal Detail:
Title:  Journal of molecular biology     Volume:  401     ISSN:  1089-8638     ISO Abbreviation:  J. Mol. Biol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-09     Completed Date:  2010-08-27     Revised Date:  2012-10-23    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  605-17     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
Laboratory of Genes and Development, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
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MeSH Terms
Cutis Laxa / genetics,  metabolism
Extracellular Matrix Proteins / chemistry*,  genetics,  metabolism
Genetic Predisposition to Disease
Macular Degeneration / genetics,  metabolism
Magnetic Resonance Spectroscopy
Models, Molecular
Mutation, Missense
Protein Conformation
Protein Folding
Grant Support
079440//Wellcome Trust; 079440//Wellcome Trust
Reg. No./Substance:
0/Extracellular Matrix Proteins; 0/FBLN5 protein, human

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