Structure of an Integrin alphaIIb beta3 Transmembrane-Cytoplasmic Heterocomplex Provides Insight Into Integrin Activation

Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17729-34. doi: 10.1073/pnas.0909589106. Epub 2009 Oct 1.

Abstract

Heterodimeric integrin adhesion receptors regulate diverse biological processes including angiogenesis, thrombosis and wound healing. The transmembrane-cytoplasmic domains (TMCDs) of integrins play a critical role in controlling activation of these receptors via an inside-out signaling mechanism, but the precise structural basis remains elusive. Here, we present the solution structure of integrin alphaIIb beta3 TMCD heterodimer, which reveals a right-handed coiled-coil conformation with 2 helices intertwined throughout the transmembrane region. The helices extend into the cytoplasm and form a clasp that differs significantly from a recently published alphaIIb beta3 TMCD structure. We show that while a point mutation in the clasp interface modestly activates alphaIIb beta3, additional mutations in the transmembrane interface have a synergistic effect, leading to extensive integrin activation. Detailed analyses and structural comparison with previous studies suggest that extensive integrin activation is a highly concerted conformational transition process, which involves transmembrane coiled-coil unwinding that is triggered by the membrane-mediated alteration and disengagement of the membrane-proximal clasp. Our results provide atomic insight into a type I transmembrane receptor heterocomplex and the mechanism of integrin inside-out transmembrane signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Cytoplasm / metabolism
  • Dimerization
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Mutagenesis, Site-Directed
  • Nuclear Magnetic Resonance, Biomolecular
  • Platelet Glycoprotein GPIIb-IIIa Complex / chemistry*
  • Platelet Glycoprotein GPIIb-IIIa Complex / genetics
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
  • Point Mutation
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection

Substances

  • Multiprotein Complexes
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Recombinant Proteins

Associated data

  • PDB/2KNC