title: alphaVbeta6 is a novel receptor for human fibrillin-1. Comparative studies of molecular determinants underlying integrin-rgd affinity and specificity.
abstract: Human fibrillin-1, the major structural protein of connective tissue 10-12 nm microfibrils, contains multiple calcium binding epidermal growth factor-like domains interspersed with transforming growth factor beta-binding protein-like (TB) domains. TB4 contains a flexible RGD loop that mediates cell adhesion via alphaVbeta3 and alpha5beta1 integrins. This study identifies integrin alphaVbeta6 as a novel cellular receptor for fibrillin-1 with a K(d) of approximately 0.45 mum. Analyses of this interaction by surface plasmon resonance and immunocytochemistry reveal different module requirements for alphaVbeta6 activation compared with those of alphaVbeta3, suggesting that a covalent linkage of an N-terminal calcium binding epidermal growth factor-like domain to TB4 can modulate alphaV integrin binding specificity. Furthermore, our data suggest alpha5beta1 is a low affinity fibrillin-1 receptor (K(d) > 1 mum), thus providing a molecular explanation for the different alpha5beta1 distribution patterns seen when human keratinocytes and fibroblasts are plated on recombinant fibrillin fragments versus those derived from the physiological ligand fibronectin. Non-focal contact distribution of alpha5beta1 suggests that its engagement by fibrillin-1 may elicit a lesser degree and/or different type of intracellular signaling compared with that seen with a high affinity ligand.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Jelena
authors.initials: J
authors.lastname: Jovanovic
authors.forename: Junichi
authors.initials: J
authors.lastname: Takagi
authors.forename: Laurence
authors.initials: L
authors.lastname: Choulier
authors.forename: Nicola G A
authors.initials: NG
authors.lastname: Abrescia
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mardon
authors.forename: Penny A
authors.initials: PA
authors.lastname: Handford
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D001665:Binding Sites; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D010446:Peptide Fragments; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D054392:Adipokines
chemical_list: D000951:Antigens, Neoplasm; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D016023:Integrins; D008840:Microfilament Proteins; D010446:Peptide Fragments; C000605722:FBN1 protein, human; D054392:Adipokines; C073878:integrin alphavbeta6