title: A helix heterodimer in a lipid bilayer: prediction of the structure of an integrin transmembrane domain via multiscale simulations.
abstract: Dimerization of transmembrane (TM) α helices of membrane receptors plays a key role in signaling. We show that molecular dynamics simulations yield models of integrin TM helix heterodimers, which agree well with available NMR structures. We use a multiscale simulation approach, combining coarse-grained and subsequent atomistic simulation, to model the dimerization of wild-type (WT) and mutated sequences of the αIIb and β3 integrin TM helices. The WT helices formed a stable, right-handed dimer with the same helix-helix interface as in the published NMR structure (PDB: 2K9J). In contrast, the presence of disruptive mutations perturbed the interface between the helices, altering the conformational stability of the dimer. The αIIb/β3 interface was more flexible than that of, e.g., glycophorin A. This is suggestive of a role for alternative packing modes of the TM helices in transbilayer signaling.
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors: Antreas C
authors: AC
authors: Kalli
authors: Benjamin A
authors: BA
authors: Hall
authors: Iain D
authors: ID
authors: Campbell
authors: Mark S P
authors: MS
authors: Sansom
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D003198:Computer Simulation; D039661:Integrin beta3 / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008322:Mammals; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D040201:Platelet Membrane Glycoprotein IIb / Q000737:chemistry*; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D015398:Signal Transduction
chemical_list: D039661:Integrin beta3; D008051:Lipid Bilayers; D008565:Membrane Proteins; D040201:Platelet Membrane Glycoprotein IIb