PT  - JOURNAL ARTICLE
AU  - Gao, Tong
AU  - Kabir, Salvin
AU  - Wu, Jinhua
TI  - Structure of Talin Bound to β2 Integrin Unveils the Molecular Mechanism of Species-Specific Integrin Activation
AID  - 10.1101/2024.05.28.596271
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.05.28.596271
4099  - http://biorxiv.org/content/early/2024/05/28/2024.05.28.596271.short
4100  - http://biorxiv.org/content/early/2024/05/28/2024.05.28.596271.full
AB  - Integrins consists of 24 species with diverse 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 detailed molecular mechanisms governing the specific recognition of different integrin species by talin 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 when compared with the β3-bound talin head, leading to distinct inter-subdomain interactions and binding affinities. Moreover, stabilizing of the C-terminal α-helix of talin head leads to enhanced affinity to integrin and its activation, suggesting a seesaw model of talin that 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 seesaw model wherein the talin head adapts specific binding modes in response to the integrin species. The two configurations differ in inter-subdomain interactions, revealing distinct cavities in each binding mode. These cavities provide novel targets for small molecules that may modulate the structural dynamics of talin and regulate its function in mediating integrin activation. Thus, our findings present exciting opportunities of the development of species-specific therapeutic agents targeting integrin activity more precisely.Competing Interest StatementThe authors have declared no competing interest.