title: Modeling transmembrane domain dimers/trimers of plexin receptors: implications for mechanisms of signal transmission across the membrane.
abstract: Single-pass transmembrane (TM) receptors transmit signals across lipid bilayers by helix association or by configurational changes within preformed dimers. The structure determination for such TM regions is challenging and has mostly been accomplished by NMR spectroscopy. Recently, the computational prediction of TM dimer structures is becoming recognized for providing models, including alternate conformational states, which are important for receptor regulation. Here we pursued a strategy to predict helix oligomers that is based on packing considerations (using the PREDDIMER webserver) and is followed by a refinement of structures, utilizing microsecond all-atom molecular dynamics simulations. We applied this method to plexin TM receptors, a family of 9 human proteins, involved in the regulation of cell guidance and motility. The predicted models show that, overall, the preferences identified by PREDDIMER are preserved in the unrestrained simulations and that TM structures are likely to be diverse across the plexin family. Plexin-B1 and -B3 TM helices are regular and tend to associate, whereas plexin-A1, -A2, -A3, -A4, -C1 and -D1 contain sequence elements, such as poly-Glycine or aromatic residues that distort helix conformation and association. Plexin-B2 does not form stable dimers due to the presence of TM prolines. No experimental structural information on the TM region is available for these proteins, except for plexin-C1 dimeric and plexin-B1 - trimeric structures inferred from X-ray crystal structures of the intracellular regions. Plexin-B1 TM trimers utilize Ser and Thr sidechains for interhelical contacts. We also modeled the juxta-membrane (JM) region of plexin-C1 and plexin-B1 and show that it synergizes with the TM structures. The structure and dynamics of the JM region and TM-JM junction provide determinants for the distance and distribution of the intracellular domains, and for their binding partners relative to the membrane. The structures suggest experimental tests and will be useful for the interpretation of future studies.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.
authors.forename: Liqun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Max F. Perutz Laboratories, Department of Structural and Computational Biology, University of Vienna, Campus Vienna Biocenter 5, Vienna, AT-1030, Austria; M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Polyansky
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America; Departments of Neurosciences, Pharmacology, Case Comprehensive Cancer Center as well as Center for Proteomics and Bioinformatics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.
authors.forename: Matthias
authors.initials: M
authors.lastname: Buck
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011956:Receptors, Cell Surface / Q000737:chemistry*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; D020033:Protein Isoforms; D011956:Receptors, Cell Surface
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