Structural basis for the autoinhibition of talin in regulating integrin activation

Mol Cell. 2008 Jul 11;31(1):124-33. doi: 10.1016/j.molcel.2008.06.011.


Activation of heterodimeric (alpha/beta) integrin transmembrane receptors by the 270 kDa cytoskeletal protein talin is essential for many important cell adhesive and physiological responses. A key step in this process involves interaction of phosphotyrosine-binding (PTB) domain in the N-terminal head of talin (talin-H) with integrin beta membrane-proximal cytoplasmic tails (beta-MP-CTs). Compared to talin-H, intact talin exhibits low potency in inducing integrin activation. Using NMR spectroscopy, we show that the large C-terminal rod domain of talin (talin-R) interacts with talin-H and allosterically restrains talin in a closed conformation. We further demonstrate that talin-R specifically masks a region in talin-PTB where integrin beta-MP-CT binds and competes with it for binding to talin-PTB. The inhibitory interaction is disrupted by a constitutively activating mutation (M319A) or by phosphatidylinositol 4,5-bisphosphate, a known talin activator. These data define a distinct autoinhibition mechanism for talin and suggest how it controls integrin activation and cell adhesion.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • CHO Cells
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Integrin beta Chains / chemistry
  • Integrin beta Chains / metabolism*
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Biological
  • Models, Molecular
  • Phosphatidylinositol 4,5-Diphosphate / pharmacology
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Talin / antagonists & inhibitors*
  • Talin / chemistry*


  • Integrin beta Chains
  • Phosphatidylinositol 4,5-Diphosphate
  • Talin