Structural mechanism of integrin inactivation by filamin

Nat Struct Mol Biol. 2015 May;22(5):383-9. doi: 10.1038/nsmb.2999. Epub 2015 Apr 6.

Abstract

Activation of heterodimeric (αβ) integrin is crucial for regulating cell adhesion. Binding of talin to the cytoplasmic face of integrin activates the receptor, but how integrin is maintained in a resting state to counterbalance its activation has remained obscure. Here, we report the structure of the cytoplasmic domain of human integrin αIIbβ3 bound to its inhibitor, the immunoglobin repeat 21 of filamin A (FLNa-Ig21). The structure reveals an unexpected ternary complex in which FLNa-Ig21 not only binds to the C terminus of the integrin β3 cytoplasmic tail (CT), as previously predicted, but also engages N-terminal helices of αIIb and β3 CTs to stabilize an inter-CT clasp that helps restrain the integrin in a resting state. Combined with functional data, the structure reveals a new mechanism of filamin-mediated retention of inactive integrin, suggesting a new framework for understanding regulation of integrin activation and adhesion.

Publication types

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

MeSH terms

  • Cell Adhesion / physiology
  • Crystallography, X-Ray
  • Filamins / metabolism*
  • Filamins / ultrastructure*
  • Humans
  • Nuclear Magnetic Resonance, Biomolecular
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
  • Platelet Glycoprotein GPIIb-IIIa Complex / ultrastructure*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Surface Plasmon Resonance
  • Talin / metabolism

Substances

  • FLNA protein, human
  • Filamins
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Talin

Associated data

  • PDB/2MTP