A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated ?IIb?3 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 ? subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin ? 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 ? 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 ?IIb?3 integrin activation, but not for kindlin binding to integrin ? 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 ?-integrin tails contribute to the ability of kindlins to activate integrins.

SUBMITTER: Bouaouina M 

PROVIDER: S-EPMC3293583 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature