title: Transmembrane signal transduction of the alpha(IIb)beta(3) integrin.
abstract: Integrins are composed of noncovalently bound dimers of an alpha- and a beta-subunit. They play an important role in cell-matrix adhesion and signal transduction through the cell membrane. Signal transduction can be initiated by the binding of intracellular proteins to the integrin. Binding leads to a major conformational change. The change is passed on to the extracellular domain through the membrane. The affinity of the extracellular domain to certain ligands increases; thus at least two states exist, a low-affinity and a high-affinity state. The conformations and conformational changes of the transmembrane (TM) domain are the focus of our interest. We show by a global search of helix-helix interactions that the TM section of the family of integrins are capable of adopting a structure similar to the structure of the homodimeric TM protein Glycophorin A. For the alpha(IIb)beta(3) integrin, this structural motif represents the high-affinity state. A second conformation of the TM domain of alpha(IIb)beta(3) is identified as the low-affinity state by known mutational and nuclear magnetic resonance (NMR) studies. A transition between these two states was determined by molecular dynamics (MD) calculations. On the basis of these calculations, we propose a three-state mechanism.
authors.affiliation: Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Gottschalk
authors.forename: Paul D
authors.initials: PD
authors.lastname: Adams
authors.forename: Axel T
authors.initials: AT
authors.lastname: Brunger
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D039421:Integrin alpha2; D039661:Integrin beta3; D008562:Membrane Glycoproteins