Spatial Coordination of Kindlin-2 with Talin Head Domain in Interaction with Integrin β Cytoplasmic Tails

Both talin head domain and kindlin-2 interact with integrin beta cytoplasmic tails, and they function in concert to induce integrin activation. Binding of talin head domain to beta cytoplasmic tails has been characterized extensively, but information on the interaction of kindin-2 with this integrin segment is limited. In this study, we systematically examine the interactions of kindlin-2 with integrin beta tails. Kindlin-2 interacted well with beta(1) and beta(3) tails but poorly with the beta(2) cytoplasmic tail. This binding selectivity was determined by the non-conserved residues, primarily the three amino acids at the extreme Cterminus of the beta(3) tail, and the sequence in beta(2) was non-permissive. The region at the C termini of integrin beta(1) and beta(3) tails recognized by kindlin-2 was a binding core of 12 amino acids. Kindlin-2 and talin head do not interact with one another but can bind simultaneously to the integrin beta(3) tail without enhancing or inhibiting the interaction of the other binding partner. Kindlin-2 itself failed to directly unclasp integrin alpha/beta tail complex, indicating that kindlin-2 must cooperate with talin to support the integrin activation mechanism.