The interface between the EGF1 and EGF2 domains is critical in integrin affinity regulation

It has been proposed that integrins adopt a bent, closed conformation with low ligand binding capability at resting state and switch into an extended, open conformation upon activation or interacting with extracellular matrix (ECM) ligand. In this study, we addressed how integrin conformational change at the β genu affects ligand binding and signaling. We discovered that swapping of the β₃ epidermal growth factor-like (EGF) domain 1 and 2 with that of β₈ greatly promoted ligand binding in β₃ β₈ chimeras. Sequence alignment indicated that β₈ integrin uniquely lacks the interface between the EGF1 and 2. Disrupting this interface of the β₃ integrin increased integrin ligand binding. Furthermore, the interface is critical for integrin affinity regulation but not downstream outside-in signaling.