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PDBsum entry 4f7g
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Cell adhesion
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PDB id
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4f7g
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References listed in PDB file
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Key reference
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Title
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A novel membrane-Dependent on/off switch mechanism of talin ferm domain at sites of cell adhesion.
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Authors
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X.Song,
J.Yang,
J.Hirbawi,
S.Ye,
H.D.Perera,
E.Goksoy,
P.Dwivedi,
E.F.Plow,
R.Zhang,
J.Qin.
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Ref.
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Cell Res, 2012,
22,
1533-1545.
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PubMed id
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Abstract
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The activation of heterodimeric (α/β) integrin transmembrane receptors by
cytosolic protein talin is crucial for regulating diverse
cell-adhesion-dependent processes, including blood coagulation, tissue
remodeling, and cancer metastasis. This process is triggered by the coincident
binding of N-terminal FERM (four-point-one-protein/ezrin/radixin/moesin) domain
of talin (talin-FERM) to the inner membrane surface and integrin β cytoplasmic
tail, but how these binding events are spatiotemporally regulated remains
obscure. Here we report the crystal structure of a dormant talin, revealing how
a C-terminal talin rod segment (talin-RS) self-masks a key integrin-binding site
on talin-FERM via a large interface. Unexpectedly, the structure also reveals a
distinct negatively charged surface on talin-RS that electrostatically hinders
the talin-FERM binding to the membrane. Such a dual inhibitory topology for
talin is consistent with the biochemical and functional data, but differs
significantly from a previous model. We show that upon enrichment with
phosphotidylinositol-4,5-bisphosphate (PIP2) - a known talin activator, membrane
strongly attracts a positively charged surface on talin-FERM and simultaneously
repels the negatively charged surface on talin-RS. Such an electrostatic
"pull-push" process promotes the relief of the dual inhibition of
talin-FERM, which differs from the classic "steric clash" model for
conventional PIP2-induced FERM domain activation. These data therefore unravel a
new type of membrane-dependent FERM domain regulation and illustrate how it
mediates the talin on/off switches to regulate integrin transmembrane signaling
and cell adhesion.
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