Conformational equilibria and intrinsic affinities define integrin activation

• Jing Li ^[1] ; Yang Su ^[1] ; Wei Xia ^[1] ; Yan Qin ^[1] ; Martin J Humphries ^[3] ; Dietmar Vestweber ^[4] ; Carlos Cabañas ^[2] ; Chafen Lu ^[1] ; Timothy A Springer ^[1]
  1. [1] Boston Children's Hospital

     Boston Children's Hospital

     City of Boston, Estados Unidos

     
  2. [2] Centro de Biología Molecular Severo Ochoa

     Centro de Biología Molecular Severo Ochoa

     Madrid, España

     
  3. [3] 3 Wellcome Trust Centre for Cell‐Matrix Research University of Manchester Manchester UK
  4. [4] 4 Max‐Planck‐Institute of Molecular Biomedicine Münster Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 5, 2017, págs. 629-645
• Idioma: inglés
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• Resumen

  • We show that the three conformational states of integrin α5β1 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 α5β1. On the surface of K562 cells, α5β1 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.