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Human fibrillin-1, the major structural protein of extracellular matrix (ECM) 10-12 nm microfibrils, is dominated by 43 calcium binding epidermal growth factor-like (cbEGF) and 7 transforming growth factor beta binding protein-like (TB) domains. Crystal structures reveal the integrin binding cbEGF22-TB4-cbEGF23 fragment of human fibrillin-1 to be a Ca(2+)-rigidified tetragonal pyramid. We suggest that other cbEGF-TB pairs within the fibrillins may adopt a similar orientation to cbEGF22-TB4. In addition, we have located a flexible RGD integrin binding loop within TB4. Modeling, cell attachment and spreading assays, immunocytochemistry, and surface plasmon resonance indicate that cbEGF22 bound to TB4 is a requirement for integrin activation and provide insight into the molecular basis of the fibrillin-1 interaction with alphaVbeta3. In light of our data, we propose a novel model for the assembly of the fibrillin microfibril and a mechanism to explain its extensibility.

Original publication

DOI

10.1016/j.str.2004.02.023

Type

Journal article

Journal

Structure

Publication Date

04/2004

Volume

12

Pages

717 - 729

Keywords

Crystallography, X-Ray, Fibrillin-1, Fibrillins, Humans, Integrins, Microfibrils, Microfilament Proteins, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Analysis, Protein, Sulfhydryl Compounds