Abstract
SummaryFERM domains are found in a diverse superfamily of signaling and adaptor proteins at membrane interfaces. They typically consist of three separately folded domains (F1, F2, F3) in a compact cloverleaf structure. The crystal structure of the N-terminal head of the integrin-associated cytoskeletal protein talin reported here reveals a novel FERM domain with a linear domain arrangement, plus an additional domain F0 packed against F1. While F3 binds β-integrin tails, basic residues in F1 and F2 are required for membrane association and for integrin activation. We show that these same residues are also required for cell spreading and focal adhesion assembly in cells. We suggest that the extended conformation of the talin head allows simultaneous binding to integrins via F3 and to PtdIns(4,5)P2-enriched microdomains via basic residues distributed along one surface of the talin head, and that these multiple interactions are required to stabilize integrins in the activated state.
Highlights
Proteins containing FERM domains are essential for a wide range of biological processes, including cell adhesion, motility, proliferation, and differentiation (Fehon et al, 2010)
The kindlin family of FERM domain proteins has a similar domain structure to the talin head (Goult et al, 2009b) and kindlins synergize with talin in integrin activation (Moser et al, 2009)
We have proposed that folding of the loop brings the F1 domain closer to the membrane, and in this way contributes to integrin activation (Goult et al, 2010)
Summary
Proteins containing FERM domains are essential for a wide range of biological processes, including cell adhesion, motility, proliferation, and differentiation (Fehon et al, 2010). A consensus FERM domain structure has emerged, largely from studies on the ezrin, radixin, moesin (ERM) family of proteins (Hamada et al, 2000; Pearson et al, 2000; Smith et al, 2003), which is characterized by a globular cloverleaf arrangement of three independently folded domains F1-3 (Pearson et al, 2000). NMR and crystallographic studies show that there is an extensive binding interface between the talin F3 domain and the membrane proximal NPxY motif and helical region of b-integrin tails, and binding is thought to disrupt the salt bridge between the a- and b-integrin tails that normally keeps integrins in the low affinity state (Anthis et al, 2009; Garcla-Alvarez et al, 2003; Wegener et al, 2007)
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