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Conformational equilibria and intrinsic affinities define integrin activation
Author(s) -
Li Jing,
Su Yang,
Xia Wei,
Qin Yan,
Humphries Martin J,
Vestweber Dietmar,
Cabañas Carlos,
Lu Chafen,
Springer Timothy A
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695803
Subject(s) - affinities , chemistry , integrin , transmembrane protein , transmembrane domain , biophysics , ligand (biochemistry) , conformational change , bent molecular geometry , stereochemistry , receptor , biochemistry , biology , organic chemistry
We show that the three conformational states of integrin α 5 β 1 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 α 5 β 1 . On the surface of K562 cells, α 5 β 1 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.