Abstract
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 β1 cytoplasmic tail and kindlin-2, a member of a family of adapters implicated in human disease pathogenesis, is mainly governed by the β1 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 β1, 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.
Highlights
Modulation of integrin/kindlin interactions can lead to human disease pathogenesis
MRNAs That Encode Mutant Integrin 1b Cytoplasmic Tails Perturb Laterality Organ Development—In a recent study we showed that antisense MO-mediated depletion of the integrin ␣V and 1b subunits leads to defective Dorsal forerunner cells (DFCs) migration during zebrafish gastrulation [12]
By using 1b mRNA overexpression in zebrafish embryos in combination with pulldown assays, we identified kindlins as candidate 1b-binding proteins to participate in ␣V1b signaling in DFCs
Summary
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. 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. Integrins represent a large family of adhesion and signaling receptors that interact with a multitude of extracellular and intracellular proteins by using various sequence motifs [4]. Modulation of these interactions can impact physiological events such as angiogenesis, hemostasis, and immune cell function [5]. The interaction of integrins with members of the kindlin family of adapter proteins has gained considerable attention because kindlins can cooperate with other intracellular proteins to activate integrins and to mediate adhesion-dependent cellular responses, in part through interactions of the kindlin FERM2
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