title: A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation.
abstract: The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin β subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin β tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin β subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells. However, the mechanisms by which kindlins impact integrin activation remain largely unknown. A notable feature of kindlins is their similarity to the integrin-binding and activating talin FERM domain. Drawing on this similarity, here we report the identification of an unstructured insert in the kindlin F1 FERM domain, and provide evidence that a highly conserved polylysine motif in this loop supports binding to negatively charged phospholipid head groups. We further show that the F1 loop and its membrane-binding motif are required for kindlin-1 targeting to focal adhesions, and for the cooperation between kindlin-1 and -2 and the talin head in αIIbβ3 integrin activation, but not for kindlin binding to integrin β tails. These studies highlight the structural and functional similarities between kindlins and the talin head and indicate that as for talin, FERM domain interactions with acidic membrane phospholipids as well β-integrin tails contribute to the ability of kindlins to activate integrins.
authors.affiliation: Department of Pharmacology and Cell Biology and Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bouaouina
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Goult
authors.forename: Clotilde
authors.initials: C
authors.lastname: Huet-Calderwood
authors.forename: Neil
authors.initials: N
authors.lastname: Bate
authors.forename: Nina N
authors.initials: NN
authors.lastname: Brahme
authors.forename: Igor L
authors.initials: IL
authors.lastname: Barsukov
authors.forename: David R
authors.initials: DR
authors.lastname: Critchley
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016608:Talin / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C475301:FERMT1 protein, human; C477322:FERMT3 protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D010743:Phospholipids; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin; C534220:kindlin-1 protein, mouse; C527802:kindlin-2 protein, mouse