Bouaouina, Mohamed, Goult, Benjamin T 
ORCID: 0000-0002-3438-2807, Huet-Calderwood, Clotilde, Bate, Neil, Brahme, Nina N, Barsukov, Igor L, Critchley, David R and Calderwood, David A ORCID: 0000-0002-0791-4142
(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.
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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 |
|---|---|
| Uncontrolled Keywords: | CHO Cells, Focal Adhesions, Animals, Humans, Cricetulus, Mice, Phospholipids, Carrier Proteins, Muscle Proteins, Cytoskeletal Proteins, Talin, Platelet Glycoprotein GPIIb-IIIa Complex, Membrane Proteins, Neoplasm Proteins, Cell Adhesion, Amino Acid Motifs, Protein Structure, Tertiary, Cricetinae |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 13 Mar 2024 09:34 |
| Last Modified: | 13 Mar 2024 09:34 |
| DOI: | 10.1074/jbc.m111.330845 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3179351 |
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