Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization.

Stephen S J Lee , Vroni Knott , Jelena Jovanovi? , Karl Harlos , Jonathan M Grimes , Laurence Choulier (1) , Helen J Mardon (2) , David I Stuart , Penny A Handford (3)

1 Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique
2 Nuffield Dept. Obstetrics and Gynaecology
3 Division of Molecular and Cellular Biochemistry

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.

Domaines: Biochimie, Biologie Moléculaire

Stephen S J Lee, Vroni Knott, Jelena Jovanovi?, Karl Harlos, Jonathan M Grimes, et al.. Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization.. Structure / Struct Fold Des; Structure (Camb ), 2004, 12 (4), pp.717-29. ⟨10.1016/j.str.2004.02.023⟩. ⟨hal-00264690⟩