title: Conformational changes in the integrin beta A domain provide a mechanism for signal transduction via hybrid domain movement.
abstract: The ligand-binding head region of integrin beta subunits contains a von Willebrand factor type A domain (betaA). Ligand binding activity is regulated through conformational changes in betaA, and ligand recognition also causes conformational changes that are transduced from this domain. The molecular basis of signal transduction to and from betaA is uncertain. The epitopes of mAbs 15/7 and HUTS-4 lie in the beta(1) subunit hybrid domain, which is connected to the lower face of betaA. Changes in the expression of these epitopes are induced by conformational changes in betaA caused by divalent cations, function perturbing mAbs, or ligand recognition. Recombinant truncated alpha(5)beta(1) with a mutation L358A in the alpha7 helix of betaA has constitutively high expression of the 15/7 and HUTS-4 epitopes, mimics the conformation of the ligand-occupied receptor, and has high constitutive ligand binding activity. The epitopes of 15/7 and HUTS-4 map to a region of the hybrid domain that lies close to an interface with the alpha subunit. Taken together, these data suggest that the transduction of conformational changes through betaA involves shape shifting in the alpha7 helix region, which is linked to a swing of the hybrid domain away from the alpha subunit.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. paul.mould@man.ac.uk
authors.forename: A Paul
authors.initials: AP
authors.lastname: Mould
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Barton
authors.forename: Janet A
authors.initials: JA
authors.lastname: Askari
authors.forename: Paul A
authors.initials: PA
authors.lastname: McEwan
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Buckley
authors.forename: Susan E
authors.initials: SE
authors.lastname: Craig
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D039641:Integrin beta Chains / Q000737:chemistry* / Q000502:physiology; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D039641:Integrin beta Chains; D008024:Ligands