Abstract
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 N-P-x-Y/F motif, triggering integrin activation. Although this motif is conserved across most integrin-β subunits, the precise molecular mechanisms governing talin’s selective recognition of different integrin species remains unclear. We determined the crystal structure of talin head in complex with the β2-integrin tail. The structure reveals a two-mode configuration featuring a “rocking” motion of the talin head FERM domain compared with its interaction with β3 integrin, resulting in distinct inter-subdomain interactions and unique cavities. Switching of the talin:β2 binding mode to the talin:β3 binding mode enhances β2-integrin affinity and boosts LFA-1-mediated natural killer cell cytotoxicity. Moreover, stabilizing of the C-terminal α-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 statement Talin exhibits significantly lower affinity with lymphocyte-rich β2 integrins compared with β3 integrins. Our results unveil the configurational preferences of the talin head when engaged β2 and β3 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
In the revised manuscript, we further analyzed the impact of talin conformation on beta2 integrin affinity and functions. Our new data reveal that shifting talin from “Mode B” to“Mode A” enhances LFA-1-mediated cytotoxicity by natural killer cells, and the D397R mutation reduces beta2:talin affinity and LFA-1 activity.
