A specific interface between integrin transmembrane helices and affinity for ligand.
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.
Luo
Bing-Hao
BH
Center for Blood Research, Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
Springer
Timothy A
TA
Takagi
Junichi
J
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D002478:Cells, Cultured; D004220:Disulfides / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D016023:Integrins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010957:Plasmids / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D000596:Amino Acids; D004220:Disulfides; D016023:Integrins; D008024:Ligands