Journal article
Marfan syndrome-causing mutations in fibrillin-1 result in gross morphological alterations and highlight the structural importance of the second hybrid domain
Journal of Biological Chemistry, Vol.281(42), pp.31854-31862
2006
Abstract
Mutations in fibrillin-1 result in Marfan syndrome, which affects the cardiovascular, skeletal and ocular systems. The multiorgan involvement and wide spectrum of associated phenotypes highlights the complex pathogenesis underlying Marfan syndrome. To elucidate the genotype to phenotype correlations, we engineered four Marfan syndrome causing mutations into a fibrillin-1 fragment encoded by exons 18 -25, a region known to interact with tropoelastin. Biophysical and biochemical approaches, including small angle x-ray scattering, analytical ultracentrifugation, and circular dichroism, were used to study the impact of these mutations upon the structure and function of the protein. Mutations G880S, C862R, and C908R, situated within the second hybrid domain, disrupted the ratio of α-helix to β-sheet leading to a more compact conformation. These data clearly demonstrate the importance of the previously uncharacterized hybrid domain in fibrillin-1 structure. In contrast, mutation K1023N situated within the linker region between the third eight cysteine motif and cbEGF 11 markedly extended the length of the fragment. However, none of the mutations affected tropoelastin binding. The profound effects of all four mutations on fragment conformation suggest that they contribute to the pathogenesis of Marfan syndrome by disrupting protein folding and its assembly into fibrillin-rich microfibrils. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Details
- Title
- Marfan syndrome-causing mutations in fibrillin-1 result in gross morphological alterations and highlight the structural importance of the second hybrid domain
- Authors
- Kieran T Mellody (Author) - University of Manchester, United KingdomLyle J Freeman (Author) - University of Manchester, United KingdomClair Baldock (Author) - University of Manchester, United KingdomThomas A Jowitt (Author) - University of Manchester, United KingdomVeronique Siegler (Author) - Cardiff University, United KingdomBertrand D E Raynal (Author) - University of Manchester, United KingdomStuart A Cain (Author) - University of Manchester, United KingdomTim J Wess (Author) - Cardiff University, United KingdomC Adrian Shuttleworth (Author) - University of Manchester, United KingdomCay M Kielty (Author) - University of Manchester, United Kingdom
- Publication details
- Journal of Biological Chemistry, Vol.281(42), pp.31854-31862
- Publisher
- American Society for Biochemistry and Molecular Biology, Inc.
- DOI
- 10.1074/jbc.M602743200
- ISSN
- 0021-9258
- Organisation Unit
- University of the Sunshine Coast, Queensland; Office of the Deputy Vice-Chancellor (Academic)
- Language
- English
- Record Identifier
- 99450625502621
- Output Type
- Journal article
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