A specific interface between integrin transmembrane helices and affinity for ligand

PLoS Biol. 2004 Jun;2(6):e153. doi: 10.1371/journal.pbio.0020153. Epub 2004 Jun 15.

Abstract

Conformational communication across the plasma membrane between the extracellular and intracellular domains of integrins is beginning to be defined by structural work on both domains. However, the role of the alpha and beta subunit transmembrane domains and the nature of signal transmission through these domains have been elusive. Disulfide bond scanning of the exofacial portions of the integrin alpha(IIbeta) and beta(3) transmembrane domains reveals a specific heterodimerization interface in the resting receptor. This interface is lost rather than rearranged upon activation of the receptor by cytoplasmic mutations of the alpha subunit that mimic physiologic inside-out activation, demonstrating a link between activation of the extracellular domain and lateral separation of transmembrane helices. Introduction of disulfide bridges to prevent or reverse separation abolishes the activating effect of cytoplasmic mutations, confirming transmembrane domain separation but not hinging or piston-like motions as the mechanism of transmembrane signaling by integrins.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / metabolism
  • Cells, Cultured
  • Disulfides / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Flow Cytometry
  • Humans
  • Immunoprecipitation
  • Integrins / genetics
  • Integrins / metabolism*
  • Integrins / physiology
  • Ligands
  • Models, Biological*
  • Molecular Sequence Data
  • Mutagenesis
  • Plasmids / genetics
  • Protein Structure, Tertiary / genetics
  • Protein Structure, Tertiary / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Transfection

Substances

  • Amino Acids
  • Disulfides
  • Integrins
  • Ligands

Associated data

  • PDB/1AFO