An internal ligand-bound, metastable state of a leukocyte integrin, ?X?2. Academic Article uri icon

abstract

  • How is massive conformational change in integrins achieved on a rapid timescale? We report crystal structures of a metastable, putative transition state of integrin ?X?2. The ?X?2 ectodomain is bent; however, a lattice contact stabilizes its ligand-binding ?I domain in a high affinity, open conformation. Much of the ?I ?7 helix unwinds, loses contact with the ?I domain, and reshapes to form an internal ligand that binds to the interface between the ? propeller and ?I domains. Lift-off of the ?I domain above this platform enables a range of extensional and rotational motions without precedent in allosteric machines. Movements of secondary structure elements in the ?2 ?I domain occur in an order different than in ?3 integrins, showing that integrin ? subunits can be specialized to assume different intermediate states between closed and open. Mutations demonstrate that the structure trapped here is metastable and can enable rapid equilibration between bent and extended-open integrin conformations and up-regulation of leukocyte adhesiveness.

publication date

  • November 25, 2013