title: Dynamics of SecY translocons with translocation-defective mutations.
abstract: The SecY/Sec61 translocon complex, located in the endoplasmic reticulum membrane of eukaryotes (Sec61) or the plasma membrane of prokaryotes (SecY), mediates the transmembrane secretion or insertion of nascent proteins. Mutations that permit the secretion of nascent proteins with defective signal sequences (Prl-phenotype), or interfere with the transmembrane orientation of newly synthesized protein segments, can affect protein topogenesis. The crystallographic structure of SecYEbeta from Methanococcus jannaschii revealed widespread distribution of mutations causing topogenesis defects, but not their molecular mechanisms. Based upon prolonged molecular dynamics simulations of wild-type M. jannaschii SecYEbeta and an extensive sequence-conservation analysis, we show that the closed state of the translocon is stabilized by hydrogen-bonding interactions of numerous highly conserved amino acids. Perturbations induced by mutation at various locations are rapidly relayed to the plug segment that seals the wild-type closed-state translocon, leading to displacement and increased hydration of the plug.
authors.affiliation: Department of Physiology and Biophysics, University of California at Irvine, Irvine, CA 92697-4560, USA.
authors.forename: Ana-Nicoleta
authors.initials: AN
authors.lastname: Bondar
authors.forename: Coral
authors.initials: C
authors.lastname: del Val
authors.forename: J Alfredo
authors.initials: JA
authors.lastname: Freites
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Tobias
authors.forename: Stephen H
authors.initials: SH
authors.lastname: White
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D019295:Computational Biology; D006860:Hydrogen Bonding; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics; D017017:Methanococcus / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D021381:Protein Transport / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D000596:Amino Acids; D026901:Membrane Transport Proteins