Structure and Interdomain Interactions of a Hybrid Domain: A Disulphide-Rich Module of the Fibrillin/LTBP Superfamily of Matrix Proteins

• Published in: Structure (London) Vol. 17; no. 5; pp. 759 - 768
• Main Authors: Jensen, Sacha A., Iqbal, Sarah, Lowe, Edward D., Redfield, Christina, Handford, Penny A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.05.2009; Cell Press
• Subjects: Amino Acid Sequence; Binding Sites; Calcium; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - metabolism; CELLBIO; Disulfides - chemistry; Disulfides - metabolism; Endothelial Growth Factors - chemistry; Endothelial Growth Factors - metabolism; Fibrillins; Latent TGF-beta Binding Proteins - chemistry; Latent TGF-beta Binding Proteins - metabolism; Microfilament Proteins - chemistry; Microfilament Proteins - metabolism; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Structure, Tertiary; PROTEINS; Structure-Activity Relationship; CELLBIO; PROTEINS
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2009.03.014

The fibrillins and latent transforming growth factor-β 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 β-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 Å 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 Ca2+ binding. These observations provide accurate constraints for models of fibrillin organization within the 10–12 nm microfibrils and provide further molecular insights into how Ca2+ binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.