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


ABSTRACT: 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.

SUBMITTER: Lee SS 

PROVIDER: S-EPMC5582136 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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

Lee Stephen S J SS   Knott Vroni V   Jovanović Jelena J   Harlos Karl K   Grimes Jonathan M JM   Choulier Laurence L   Mardon Helen J HJ   Stuart David I DI   Handford Penny A PA  

Structure (London, England : 1993) 20040401 4


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 a  ...[more]

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