High integrin α V β 6 affinity reached by hybrid domain deletion slows ligand-binding on-rate

Significance Integrins are complex multidomain adhesion molecules. We study how their affinity and binding kinetics for extracellular ligands are regulated, which is essential to enable integrins to communicate with the cytoskeleton. We show that the hybrid domain, which interfaces with the βI domain, strongly regulates affinity for ligand, which binds to a distal face of the βI domain. At high integrin affinity, the ligand binding on-rate goes down. We propose that integrins bind ligand in their low-affinity state, which has a wider ligand-binding pocket, and then convert to their high-affinity state, which has a tighter pocket.