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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents

ID: 732093.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
Relating conformation to function in integrin alpha5beta1
Authors:Su, Y.; Xia, W.; Li, J.; Walz, T.; Humphries, M. J.; Vestweber, D.; Cabanas, C.; Lu, C.; Springer, T. A.
Date of Publication (YYYY-MM-DD):2016-07-05
Title of Journal:Proc Natl Acad Sci u S A
Issue / Number:27
Start Page:E3872
End Page:3881
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Whether beta1 integrin ectodomains visit conformational states similarly to beta2 and beta3 integrins has not been characterized. Furthermore, despite a wealth of activating and inhibitory antibodies to beta1 integrins, the conformational states that these antibodies stabilize, and the relation of these conformations to function, remain incompletely characterized. Using negative-stain electron microscopy, we show that the integrin alpha5beta1 ectodomain adopts extended-closed and extended-open conformations as well as a bent conformation. Antibodies SNAKA51, 8E3, N29, and 9EG7 bind to different domains in the alpha5 or beta1 legs, activate, and stabilize extended ectodomain conformations. Antibodies 12G10 and HUTS-4 bind to the beta1 betaI domain and hybrid domains, respectively, activate, and stabilize the open headpiece conformation. Antibody TS2/16 binds a similar epitope as 12G10, activates, and appears to stabilize an open betaI domain conformation without requiring extension or hybrid domain swing-out. mAb13 and SG/19 bind to the betaI domain and betaI-hybrid domain interface, respectively, inhibit, and stabilize the closed conformation of the headpiece. The effects of the antibodies on cell adhesion to fibronectin substrates suggest that the extended-open conformation of alpha5beta1 is adhesive and that the extended-closed and bent-closed conformations are nonadhesive. The functional effects and binding sites of antibodies and fibronectin were consistent with their ability in binding to alpha5beta1 on cell surfaces to cross-enhance or inhibit one another by competitive or noncompetitive (allosteric) mechanisms.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Rockefeller University, New York, NY 10065; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; Max Planck Institute of Molecular Biomedicine, 48149 Muenster, Germany; Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; timothy.springer@childrens.harvard.edu.
Identifiers:ISSN:1091-6490 (Electronic) 0027-8424 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/27317747 [ID No:2]
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