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

Background: The talin and kindlin play indispensable roles in integrin activation. Results: The C-terminal 12 amino acids of β1 and β3 integrins mediate kindlin-2 binding. Conclusion: Kindlin-2 binding to the extreme C terminus allows β subunits to accommodate both kindlin-2 and talin. Significance: Binding of talin and kindlin-2 to distinct sites in integrins regulates receptor activation, a pivotal event in cellular responses. Both talin head domain and kindlin-2 interact with integrin β cytoplasmic tails, and they function in concert to induce integrin activation. Binding of talin head domain to β 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 β tails. Kindlin-2 interacted well with β1 and β3 tails but poorly with the β2 cytoplasmic tail. This binding selectivity was determined by the non-conserved residues, primarily the three amino acids at the extreme C terminus of the β3 tail, and the sequence in β2 was non-permissive. The region at the C termini of integrin β1 and β3 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 β3 tail without enhancing or inhibiting the interaction of the other binding partner. Kindlin-2 itself failed to directly unclasp integrin α/β tail complex, indicating that kindlin-2 must cooperate with talin to support the integrin activation mechanism.