Backbone dynamics of a cbEGF domain pair in the presence of calcium

Werner, Jörn M., Knott, Vroni, Handford, Penny A., Campbell, Iain D. and Downing, A.Kristina (2000) Backbone dynamics of a cbEGF domain pair in the presence of calcium. Journal of Molecular Biology, 296 (4), 1065-1078. (doi:10.1006/jmbi.1999.3513).

Abstract

Calcium binding (cb) epidermal growth factor-like (EGF) domains are found in a wide variety of extracellular proteins with diverse functions. In several proteins, including the fibrillins (1 and 2), the low-density lipoprotein receptor, the Notch receptor and related molecules, these domains are organised as multiple tandem repeats. The functional importance of calcium-binding by EGF domains has been underscored by the identification of missense mutations associated with defective calcium-binding, which have been linked to human diseases. Here, we present 15N backbone relaxation data for a pair of cbEGF domains from fibrillin-1, the defective protein in the Marfan syndrome. The data were best fit using a symmetric top model, confirming the extended conformation of the cbEGF domain pair. Our data demonstrate that calcium plays a key role in stabilising the rigidity of the domain pair on the pico- to millisecond time-scale. Strikingly, the most dynamically stable region of the construct is centred about the domain interface. These results provide important insight into the properties of intact fibrillin-1, the consequences of Marfan syndrome causing mutations, and the ultrastructure of fibrillins and other extracellular matrix proteins.

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Contributors

Author: Jörn M. Werner

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