The activation of integrins is crucial for regulating the attachment of a cell to the extracellular matrix (ECM) and modulating the transmission of forces and signals required for locomotion. Previous studies have established that the PTB-like F3 subdomain of the adaptor protein talin binds to integrin tails leading to integrin activation. Now in Cell, Iain Campbell and colleagues describe the structural basis of integrin activation by talin furthering our understanding of how this process might be manipulated.

The authors developed a chimeric peptide suitable for high-resolution studies that comprises the membrane proximal (MP) region of ₃ integrin and the integrin membrane distal (MD)-mimicking region of phosphatidylinositol phosphate kinase type I, which interact with the F3 domain of talin. The structure of this talin F3-peptide complex reveals new sites of contact between the MP region of ₃ integrins and talin. Phe727 and Phe730 of the ₃ tail make intimate contact with the F3 domain; mutating these residues to Ala results in an integrin mutant that is only weakly activated by talin.

Similarly, mutation of any of the MP contact residues in the talin F3 domain (Leu325Arg, Ser365Asp, Ser379Asp or Gln381Val) diminished its ability to activate IIb₃ integrin in transfected Chinese hamster ovary (CHO) cells. However, as binding to the MD region of the ₃ peptide was unchanged, the authors investigated whether these talin mutants could compete with endogenous talin and therefore, inhibit integrin activation. Indeed, all four mutants blocked the activation of a talin-dependent, constitutively active chimeric integrin expressed in CHO cells. Interestingly, this dominant-negative effect could be recapitulated with other PTB domain-containing proteins, such as DOK1, that are able to bind to the MD but not the MP region of the ₃ integrin tail. These findings are consistent with the idea that PTB domain-containing proteins compete with talin for binding to the MD site but do not interact with the MP region of ₃ which is critical for integrin activation.

The structures of the DOK1 and talin PTB domains differ in a short region between strands S1 and S2. It seems that the flexible loop that accepts the ₃ Phe727 and Phe730 in talin's PTB domain is responsible for its unique ability to activate integrins. Moreover, these results indicate that the affinity of other PTB-containing proteins for the MD region of ₃ could be important for regulating integrin activity in vivo.

Figuring out the precise mechanisms of integrin regulation is particularly interesting from a therapeutic point of view as integrins are involved in a wide variety of pathological events such as atherosclerosis and cancer. The structure of the integrin activation interface described in this paper could be an excellent starting point for the design of new drugs aimed at disrupting integrin activation.

Author: Monica Hoyos-Flight