C-terminal COOH of Integrin β1 Is Necessary for β1 Association with the Kindlin-2 Adapter Protein

Background: Modulation of integrin/kindlin interactions can lead to human disease pathogenesis. Results: Interaction between integrin 1 and the kindlin-2 is mainly governed by the 1 C-terminal carboxylate moiety. Conclusion: The interaction chemistry identified here between integrin 1 and kindlin-2 appears to represent a novel protein-protein interaction mode. Significance: The unusual integrin 1/kindlin-2 association chemistry sheds new light on this aspect of integrin biology. Protein-protein interactions are driving forces in cellular processes. As a prime example, transmembrane integrins link extracellular matrix and intracellular proteins, resulting in bidirectional signaling that regulates cell migration, proliferation, differentiation, and survival. Here we provide the first evidence that interaction between the integrin 1 cytoplasmic tail and kindlin-2, a member of a family of adapters implicated in human disease pathogenesis, is mainly governed by the 1 C-terminal carboxylate moiety and is required for laterality organ development in zebrafish. Affinity measurements indicate that this unusual protein-protein interaction mode is coordinated by a putative carboxylate-binding motif in the kindlin-2 FERM subdomain F3. Contrary to the C terminus of proteins that engage PDZ domains, the C-terminal three residues of 1, per se, do not contribute to kindlin-2 binding or to laterality organ development. Thus, by employing zebrafish as an in situ physiological tool to correlate protein structure and function, we have discovered an unexpected association chemistry between an integrin and a key adapter involved in integrin signaling.