4F7G

Crystal structure of talin autoinhibition complex

Summary for 4F7G

• Entry DOI: 10.2210/pdb4f7g/pdb
• Descriptor: Talin-1 (3 entities in total)
• Functional Keywords: alpha-helix bundle, integrin activation, cell adhesion
• Biological source: Mus musculus (mouse); More
• Cellular location: Cell projection, ruffle membrane; Peripheral membrane protein; Cytoplasmic side (By similarity): P26039 P26039
• Total number of polymer chains: 2
• Total formula weight: 48472.89

Authors

Song, X.,Qin, J.,Ye, S.,Zhang, R. (deposition date: 2012-05-16, release date: 2012-07-04, Last modification date: 2024-02-28)

Primary citation

Song, X.,Yang, J.,Hirbawi, J.,Ye, S.,Perera, H.D.,Goksoy, E.,Dwivedi, P.,Plow, E.F.,Zhang, R.,Qin, J.
A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion.
Cell Res., 22:1533-1545, 2012

PubMed Abstract: 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.

PubMed: 22710802
DOI: 10.1038/cr.2012.97

Experimental method

X-RAY DIFFRACTION (2.05 Å)