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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents



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ID: 744129.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
Conformational equilibria and intrinsic affinities define integrin activation
Authors:Li, J.; Su, Y.; Xia, W.; Qin, Y.; Humphries, M. J.; Vestweber, D.; Cabanas, C.; Lu, C.; Springer, T. A.
Date of Publication (YYYY-MM-DD):2017-03-01
Title of Journal:EMBO J
Volume:36
Issue / Number:5
Start Page:629
End Page:645
Review Status:Internal review
Audience:Not Specified
Abstract / Description:We show that the three conformational states of integrin alpha5beta1 have discrete free energies and define activation by measuring intrinsic affinities for ligand of each state and the equilibria linking them. The 5,000-fold higher affinity of the extended-open state than the bent-closed and extended-closed states demonstrates profound regulation of affinity. Free energy requirements for activation are defined with protein fragments and intact alpha5beta1 On the surface of K562 cells, alpha5beta1 is 99.8% bent-closed. Stabilization of the bent conformation by integrin transmembrane and cytoplasmic domains must be overcome by cellular energy input to stabilize extension. Following extension, headpiece opening is energetically favored. N-glycans and leg domains in each subunit that connect the ligand-binding head to the membrane repel or crowd one another and regulate conformational equilibria in favor of headpiece opening. The results suggest new principles for regulating signaling in the large class of receptors built from extracellular domains in tandem with single-span transmembrane domains.
Free Keywords:Cell Line; Humans; Integrin alpha5beta1/*chemistry/*metabolism; Models, Molecular; Protein Binding; Protein Conformation; Thermodynamics; *N-glycan; *affinity; *conformation; *integrin; *thermodynamics
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK. Max-Planck-Institute of Molecular Biomedicine, Munster, Germany. Centro de Biologia Molecular Severo Ochoa (CSIC-UAM) and Departamento de Microbiologia I Facultad de Medicina UCM, Madrid, Spain. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA timothy.springer@childrens.harvard.edu.
Identifiers:ISSN:1460-2075 (Electronic) 0261-4189 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28122868 [ID No:2]
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