Disease relevance of SEC61

• Moreover, Sec61-gamma and SSS1p are structurally related to SecEp of E. coli and to putative homologues in various other bacteria [1].

High impact information on SEC61

• In vitro assembled yeast ribosome-nascent chain complexes (RNCs) containing a signal sequence in the nascent chain were immunopurified and reconstituted with the purified protein-conducting channel (PCC) of yeast endoplasmic reticulum, the Sec61 complex [2].
• Together with the TRAM protein, Sec61p provides a site in the membrane, at the interface of channel and lipid, through which a TM domain can dynamically equilibrate between the lipid and aqueous phases, depending on the hydrophobicity of the TM domain and the length of the polypeptide segment tethering it to the ribosome [3].
• While bound to Sec61p, the signal sequence forms a helix that is contacted on one side by Sec62p and Sec71p [4].
• Cross-linking studies indicate that the signal sequence interacts in a Kar2p- and ATP-independent reaction with Sec61p, the multispanning membrane component of the protein-conducting channel, by intercalation into transmembrane domains 2 and 7 [4].
• Oligomeric rings of the Sec61p complex induced by ligands required for protein translocation [5].

Biological context of SEC61

• This enzyme, UBC6, localizes to the endoplasmic reticulum (ER), with the catalytic domain facing the cytosol. ubc6 loss-of-function mutants suppress the protein translocation defect caused by a mutation in SEC61, which encodes a key component of a multisubunit protein translocation apparatus of the ER [6].
• The SEC61, SEC62 and SEC63 yeast gene products are membrane components of the apparatus that catalyses protein translocation into the endoplasmic reticulum (ER) [7].
• Some form of interaction among the SEC61 (Deshaies, R. J., and R. Schekman. 1987. J. Cell Biol. 105:633-645), SEC62 and SEC63 gene products is suggested by the observation that haploid cells containing any pair of the mutations are inviable at 24 degrees C and show a marked enhancement of the translocation defect [8].
• In addition, loss of the SEC61-related gene, SSH1, also has no effect on peroxisome biogenesis [9].
• The sequence of a 15 769 bp segment of Pichia anomala identifies the SEC61 and FBP1 genes and five new open reading frames [10].

Anatomical context of SEC61

• Like the Sec61p complex, the Ssh1p complex interacts with membrane-bound ribosomes, but it does not associate with the Sec62-Sec63p complex to form a heptameric Sec complex [11].
• Yeast microsomes contain a heptameric Sec complex involved in post-translational protein transport that is composed of a heterotrimeric Sec61p complex and a tetrameric Sec62-Sec63 complex [11].
• Cotranslational protein transport into dog pancreas microsomes involves the Sec61p complex plus a luminal heat shock protein 70 [12].
• This requires retrograde transport of the respective proteins from the endoplasmic reticulum back to the cytosol via the Sec61 translocon [13].
• These data are in accordance with a model in which tail-anchored proteins can be extracted from membranes independently of Sec61p [14].

Associations of SEC61 with chemical compounds

• Glycopeptide export was severely impaired, however, in several sec61 mutants that were only marginally defective in misfolded protein export [15].
• Sec63p associates with several other proteins, including Sec61p, a 31.5-kDa glycoprotein, and a 23-kDa protein, and together with these proteins may constitute part of the polypeptide translocation apparatus [16].
• cDNA cloning of a Sec61 homologue from the cryptomonad alga Pyrenomonas salina [17].

Physical interactions of SEC61

• Two of the ORFs code for the well-characterized genes SEC61 (which codes for the core subunit of the ER translocation complex) and FBP1 (encoding fructose-1,6-bisphosphatase) [10].
• SSS1 encodes a stabilizing component of the Sec61 subcomplex of the yeast protein translocation apparatus [18].
• The OT subunit Wbp1p was found to interact very strongly with Sec61p and Sbh1p and weakly with Sss1p [19].

Regulatory relationships of SEC61

• In vivo insertion of the hybrid protein bearing the first signal anchor sequence of uracil permease into the endoplasmic reticulum membrane was severely blocked in sec61 and sec62 translocation mutants [20].
• Oligomer formation by the reconstituted Sec61p complex is stimulated by its association with ribosomes or the Sec62/63p complex [5].

Other interactions of SEC61

• Here we show that Sec61, Sec62 and Sec63 are assembled with two additional proteins into a multisubunit membrane-associated complex [21].
• The first extragenic Sec sixty-one suppressor, SSS1, is an essential single copy gene whose overexpression restores translocation in the sec61 mutant [7].
• Previously, we identified SEB1/SBH1, encoding the beta subunit of the Sec61p ER translocation complex, as a multicopy suppressor of the sec15-1 mutant, defective for one subunit of the exocyst complex [22].
• The Candida albicans orthologue of the SPC3 gene, which encodes one of the subunits essential for the activity of the signal peptidase complex in Saccharomyces cerevisiae, was isolated by complementation of a thermosensitive mutation in the S. cerevisiae SEC61 gene [23].
• Complete import of CPY into the lumen of the ER requests a new targeting mechanism for retrograde transport of the malfolded enzyme through the Sec61 channel to occur [24].

Analytical, diagnostic and therapeutic context of SEC61

• We show by electron microscopy that purified mammalian and yeast Sec61p complexes in detergent form cylindrical oligomers with a diameter of approximately 85 A and a central pore of approximately 20 A. Each oligomer contains 3-4 heterotrimers [5].
• Based on a co-immunoprecipitation of major histocompatibility complex (MHC) class I heavy-chain breakdown intermediates with the translocon subunit Sec61p, it was speculated that Sec61p maybe involved in retrograde transport [25].
• Cryo-electron microscopy of the ribosome-Sec61 complex and a three-dimensional reconstruction showed that the Sec61 oligomer is attached to the large ribosomal subunit by a single connection [26].

References