Disruption of disulfide-restriction at integrin knees induces activation and ligand-independent signaling of α4β7

Abstract

Control of integrin activation and signaling plays critical roles in cell adhesion, spreading, and migration. Here, we report that selective breakage of two conserved disulfide bonds located at the knees of integrin, α4C589–C594 and β7C494–C526, induced α4β7 activation. This activated α4β7 had a unique structure different from the typical extended conformation of active integrin. In addition, these activated α4β7 integrins spontaneously clustered on the cell membrane and triggered integrin downstream signaling independent of ligand binding. Although these disulfide bonds were not broken during α4β7 activation by inside-out signaling or Mn2+, they could be specifically reduced by 0.1 mM dithiothreitol, a reducing strength that could be produced in vivo under certain conditions. Our findings reveal a novel mechanism of integrin activation under specific reducing conditions by which integrin can signal and promote cell spreading in the absence of ligand.