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Novel activating and inactivating mutations in the integrin beta1 subunit A domain.
Barton, Stephanie J; Travis, Mark A; Askari, Janet A; Buckley, Patrick A; Craig, Susan E; Humphries, Martin J; Mould, A Paul.
Afiliação
  • Barton SJ; The Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK.
Biochem J ; 380(Pt 2): 401-7, 2004 Jun 01.
Article em En | MEDLINE | ID: mdl-14967067
The ligand-binding activity of integrins is regulated by shape changes that convert these receptors from a resting (or inactive) state to an active state. However, the precise conformational changes that take place in head region of integrins (the site of ligand binding) during activation are not well understood. The portion of the integrin beta subunit involved in ligand recognition contains a von Willebrand factor type A domain, which comprises a central beta-sheet surrounded by seven alpha helices (alpha1-alpha7). Using site-directed mutagenesis, we show here that point mutation of hydrophobic residues in the alpha1 and alpha7 helices (which would be predicted to increase the mobility of these helices) markedly increases the ligand-binding activity of both integrins alpha5beta1 and alpha4beta1. In contrast, mutation of a hydrophilic residue near the base of the alpha1 helix decreases activity and also suppresses exposure of activation epitopes on the underlying hybrid domain. Our results provide new evidence that shifts of the alpha1 and alpha7 helices are involved in activation of the A domain. Although these changes are grossly similar to those defined in the A domains found in some integrin alpha subunits, movement of the alpha1 helix appears to play a more prominent role in betaA domain activation.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos / Integrina beta1 / Mutação Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2004 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos / Integrina beta1 / Mutação Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2004 Tipo de documento: Article