Integrins are a family of heterodimeric (¦Á+¦Â) adhesion receptors that play key roles in many cellular processes. Integrins are unusual in that their functions can be modulated from both outside and inside the cell. Inside-out signaling is mediated by binding adaptor proteins to the flexible cytoplasmic tails of the ¦Á- and ¦Â-integrin subunits. Talin is one well-known intracellular activator, but various other adaptors bind to integrin tails, including
14-
3-
3-¦
Æ, ?a member of the
14-
3-
3 family of dimeric proteins that have a preference for binding phosphorylated sequence motifs. Phosphorylation of a threonine in the ¦Â2 integrin tail has been shown to modulate ¦Â2/
14-
3-
3-¦Æ interactions, and recently, the ¦Á4 integrin tail was reported to bind to
14-
3-
3-¦Æ and associate with paxillin in a ternary complex that is regulated by serine phosphorylation.
Here, we use a range of biophysical techniques to characterize interactions between 14-3-3-¦Æ and the cytoplasmic tails of ¦Á4, ¦Â1, ¦Â2 and ¦Â3 integrins. The X-ray structure of the 14-3-3-¦Æ/¦Á4 complex indicates a canonical binding mode for the ¦Á4 phospho-peptide, but unexpected features are also observed: residues outside the consensus 14-3-3-¦Æ binding motif are shown to be essential for an efficient interaction; in contrast, a short ¦Â2 phospho-peptide is sufficient for high-affinity binding to 14-3-3-¦Æ. In addition, we report novel 14-3-3-¦Æ/integrin tail interactions that are independent of phosphorylation. Of the integrin tails studied, the strongest interaction with 14-3-3-¦Æ is observed for the ¦Â1A variant. In summary, new insights about 14-3-3-¦Æ/integrin tail interactions that have implications for the role of these molecular associations in cells are described.
