A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation

Bouaouina, Mohamed and Goult, Benjamin T and Huet-Calderwood, Clotilde and Bate, Neil and Brahme, Nina N and Barsukov, Igor L and Critchley, David R and Calderwood, David A (2012) A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation. The Journal of biological chemistry, 287 (10). pp. 6979-6990. ISSN 1083-351X. (doi:https://doi.org/10.1074/jbc.M111.330845) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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.

Item Type:	Article
Subjects:	Q Science > QH Natural history > QH301 Biology
Divisions:	Faculties > Sciences > School of Biosciences
Depositing User:	Ben Goult
Date Deposited:	07 Aug 2014 16:05 UTC
Last Modified:	30 Mar 2015 10:54 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/42115 (The current URI for this page, for reference purposes)