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The fibrillins and latent transforming growth factor-beta binding proteins (LTBPs) form a superfamily of structurally-related proteins consisting of calcium-binding epidermal growth factor-like (cbEGF) domains interspersed with 8-cysteine-containing transforming growth factor beta-binding protein-like (TB) and hybrid (hyb) domains. Fibrillins are the major components of the extracellular 10-12 nm diameter microfibrils, which mediate a variety of cell-matrix interactions. Here we present the crystal structure of a fibrillin-1 cbEGF9-hyb2-cbEGF10 fragment, solved to 1.8 A resolution. The hybrid domain fold is similar, but not identical, to the TB domain fold seen in previous fibrillin-1 and LTBP-1 fragments. Pairwise interactions with neighboring cbEGF domains demonstrate extensive interfaces, with the hyb2-cbEGF10 interface dependent on Ca(2+) binding. These observations provide accurate constraints for models of fibrillin organization within the 10-12 nm microfibrils and provide further molecular insights into how Ca(2+) binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.

Original publication

DOI

10.1016/j.str.2009.03.014

Type

Journal article

Journal

Structure

Publication Date

13/05/2009

Volume

17

Pages

759 - 768

Keywords

Amino Acid Sequence, Binding Sites, Calcium, Calcium-Binding Proteins, Disulfides, Endothelial Growth Factors, Fibrillins, Latent TGF-beta Binding Proteins, Microfilament Proteins, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Structure, Tertiary, Structure-Activity Relationship