title: 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.
authors.affiliation: The Henry Wellcome Building of Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Stephen S J
authors.initials: SS
authors.lastname: Lee
authors.forename: Vroni
authors.initials: V
authors.lastname: Knott
authors.forename: Jelena
authors.initials: J
authors.lastname: Jovanović
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Grimes
authors.forename: Laurence
authors.initials: L
authors.lastname: Choulier
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mardon
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: Penny A
authors.initials: PA
authors.lastname: Handford
mesh_terms: D018360:Crystallography, X-Ray; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D016023:Integrins / Q000378:metabolism; D020894:Microfibrils / Q000737:chemistry* / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein; D013438:Sulfhydryl Compounds; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D016023:Integrins; D008840:Microfilament Proteins; D013438:Sulfhydryl Compounds; C000605722:FBN1 protein, human; D054392:Adipokines