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Human Molecular Genetics, 2000, Vol. 9, No. 13 1987-1994
© 2000 Oxford University Press

Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context

Aileen J. McGettrick, Vroni Knott, Anthony Willis1 and Penny A. Handford+

Department of Biochemistry and 1MRC Immunochemistry Unit, University of Oxford, South Parks Road, Oxford OX1 3QU, UK

Mutations in the human fibrillin-1 (FBN-1) gene cause Marfan syndrome (MFS), an autosomal dominant disease of connective tissue. Fibrillin-1, a 350 kDa extracellular calcium binding protein, is a major structural component of 10–12 nm microfibrils and consists predominantly of two repeated module types: the calcium binding epidermal growth factor-like (cbEGF) domain and the transforming growth factor ß1 binding protein-like (TB) domain. A group of reported FBN-1 mutations is predicted to reduce calcium binding to cbEGF domains by removal of a side chain ligand for calcium. These mutations occur in two protein domain contexts, either in a cbEGF preceded by a TB domain or in a cbEGF preceded by another cbEGF domain. In this study we have used three proteases to probe structural changes caused by an N2144S MFS calcium binding mutation in a TB6–cbEGF32 and a cbEGF32–33 domain pair, and an N2183S mutation in the cbEGF32–33 pair. N-terminal sequence analysis of domain pairs digested in the presence and absence of calcium show that: (i) domain interactions between TB6 and cbEGF32 are calcium independent, despite the presence of a calcium binding site in cbEGF32; (ii) domain interactions between cbEGF32 and cbEGF33 are calcium dependent; and (iii) an N->S mutation causes increased proteolytic susceptibility only when located in cbEGF33, consistent with a key role for interdomain calcium binding in rigidifying cbEGF domain linkages. These data demonstrate for the first time that the structural consequences of calcium binding mutations in fibrillin-1 cbEGF domains can be influenced by domain context.

+ To whom correspondence should be addressed. Tel: +44 1865 285347; Fax: +44 1865 275259; Email: penny@bioch.ox.ac.uk


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