Molecular Basis of β2 Integrin Activation by Talin Unveils Species-Specific Mechanisms of Integrin Signaling

Integrins consist of 24 species, each with unique tissue-expression profiles and distinct biological functions. The {beta} subunit of integrin interacts with the FERM-folded head domain of talin through an N-P-x-Y/F motif, triggering integrin activation. Although this motif is conserved across most integrin-{beta} subunits, the precise molecular mechanisms governing talins selective recognition of different integrin species remains unclear. We determined the crystal structure of talin head in complex with the {beta}2-integrin tail. The structure reveals a two-mode configuration featuring a "rocking" motion of the talin head FERM domain compared with its interaction with {beta}3 integrin, resulting in distinct inter-subdomain interactions and unique cavities. Switching of the talin:{beta}2 binding mode to the talin:{beta}3 binding mode enhances {beta}2-integrin affinity and boosts LFA-1-mediated natural killer cell cytotoxicity. Moreover, stabilizing of the C-terminal -helix in the talin head enhances its affinity to integrin and its activation. Together, our data elucidate the structural basis by which talin orchestrates its function in mediating integrin activation in a species-specific manner. Significance statementTalin exhibits significantly lower affinity with lymphocyte-rich {beta}2 integrins compared with {beta}3 integrins. Our results unveil the configurational preferences of the talin head when engaged {beta}2 and {beta}3 integrins. We introduce a two-mode seesaw model wherein the talin head adapts specific binding modes in response to distinct integrin species. The two configurations differ in inter-subdomain interactions, revealing unique cavities and distinct binding dynamics in each binding mode. Thus, our findings present exciting opportunities of the development of species-specific therapeutic agents targeting integrin activity more precisely by orchestrating the structural dynamics of talin.