The phosphotyrosine binding-like domain of talin activates integrins

Abstract

Cellular regulation of the ligand binding affinity of integrin adhesion receptors (integrin activation) depends on the integrin β cytoplasmic domains (tails). The head domain of talin binds to several integrin β tails and activates integrins. This head domain contains a predicted FERM domain composed of three subdomains (F1, F2, and F3). An integrin-activating talin fragment was predicted to contain the F2 and F3 subdomains. Both isolated subdomains bound specifically to the integrin β3 tail. However, talin F3 bound the β3 tail with a 4-fold higher affinity than talin F2. Furthermore, expression of talin F3 (but not F2) in cells led to activation of integrin αIIbβ3. A molecular model of talin F3 indicated that it resembles a phosphotyrosine-binding (PTB) domain. PTB domains recognize peptide ligands containing β turns, often formed by NPXY motifs. NPX(Y/F) motifs are highly conserved in integrin β tails, and mutations that disrupt this motif interfere with both integrin activation and talin binding. Thus, integrin binding to talin resembles the interactions of PTB domains with peptide ligands. These resemblances suggest that the activation of integrins requires the presence of a β turn at NPX(Y/F) motifs conserved in integrin β cytoplasmic domains.