Activation of integrin alphaIIbbeta3 by modulation of transmembrane helix associations.
Transmembrane helices of integrin alpha and beta subunits have been implicated in the regulation of integrin activity. Two mutations, glycine-708 to asparagine-708 (G708N)and methionine-701 to asparagine-701, in the transmembrane helix of the beta3 subunit enabled integrin alphaIIbbeta3 to constitutively bind soluble fibrinogen. Further characterization of the G708N mutant revealed that it induced alphaIIbbeta3 clustering and constitutive phosphorylation of focal adhesion kinase. This mutation also enhanced the tendency of the transmembrane helix to form homotrimers. These results suggest that homomeric associations involving transmembrane domains provide a driving force for integrin activation. They also suggest a structural basis for the coincidence of integrin activation and clustering.
Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Renhao
R
Li
Neal
N
Mitra
Holly
H
Gratkowski
Gaston
G
Vilaire
Rustem
R
Litvinov
Chandrasekaran
C
Nagasami
John W
JW
Weisel
James D
JD
Lear
William F
WF
DeGrado
Joel S
JS
Bennett
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001704:Biopolymers; D016466:CHO Cells; D002448:Cell Adhesion; D002462:Cell Membrane / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D005340:Fibrinogen / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008024:Ligands; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011940:Receptor Aggregation
D000911:Antibodies, Monoclonal; D001704:Biopolymers; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016650:Fluorescein-5-isothiocyanate