Molecular basis of β2 integrin activation by talin unveils subunit-specific mechanisms of integrin signaling.

Integrins consist of 24 species, each with unique tissue expression profiles and distinct biological functions. The β subunit of integrin interacts with the FERM-folded head domain of talin through an NPxY/F motif, triggering integrin activation. Although this motif is conserved across most integrin-β subunits, the precise molecular mechanism governing talin's selective recognition of different integrin-β subunits remains unclear. We identify two distinct configurations of the talin head when interacting with β2 and β3 integrins, providing critical insights into subunit-specific recognition of integrins. Structural studies reveal that mutations at the subdomain interface of the talin head can shift its β2-bound configuration to a β3-bound configuration. This shift enhances β2-integrin affinity, leading to increased lymphocyte function-associated antigen-1 (LFA-1)-mediated natural killer cell activity. Together, our data elucidate the structural basis of talin's role in mediating integrin activation in a subunit-specific manner and advance our understanding of how talin may regulate diverse functions of various integrin species.