A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion

Cell Res. 2012 Nov;22(11):1533-45. doi: 10.1038/cr.2012.97. Epub 2012 Jun 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Cell Adhesion*
  • Cell Communication
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Integrin beta Chains / metabolism*
  • Integrins / chemistry
  • Integrins / metabolism*
  • Ligands
  • Models, Molecular
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • Static Electricity
  • Talin / chemistry*
  • Talin / metabolism*

Substances

  • Cytoskeletal Proteins
  • Integrin beta Chains
  • Integrins
  • Ligands
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Cell Surface
  • Talin