title: C-terminal COOH of integrin β1 is necessary for β1 association with the kindlin-2 adapter protein.
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.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093-0726.
authors.forename: Paul
authors.initials: P
authors.lastname: Fitzpatrick
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093-0726.
authors.forename: Sanford J
authors.initials: SJ
authors.lastname: Shattil
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093-0726. Electronic address: aablooglu@ucsd.edu.
authors.forename: Ararat J
authors.initials: AJ
authors.lastname: Ablooglu
mesh_terms: D000818:Animals; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C477322:FERMT3 protein, human; D019012:Integrin beta1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D029961:Zebrafish Proteins
keywords: Cell-Cell Interaction; Development; FERM; Integrins; Kindlin; PDZ; Protein-Protein Interactions; Zebrafish; cd29; cd51