High impact information on SEC61A1

• P58(IPK) recruits HSP70 chaperones to the cytosolic face of Sec61 and can be crosslinked to proteins entering the ER that are delayed at the translocon [1].
• Here, we report that P58(IPK)/DNAJC3, a UPR-responsive gene previously implicated in translational control, encodes a cytosolic cochaperone that associates with the ER protein translocation channel Sec61 [1].
• The requirement for SRP can, under certain experimental conditions, be circumvented by depletion of NAC, a heterodimeric complex that can block the tight association of nascent chain-ribosome complexes to the Sec61p complex in the ER membrane [2].
• The conserved protein-conducting channel, referred to as the Sec61 channel in eukaryotes or the SecY channel in eubacteria and archaea, translocates proteins across cellular membranes and integrates proteins containing hydrophobic transmembrane segments into lipid bilayers [3].
• In eukaryotes, proteins are inserted into the endoplasmic reticulum using the signal recognition particle (SRP) and the SRP receptor, as well as the integral membrane Sec61 trimeric complex (composed of alpha, beta and gamma subunits) [4].

Biological context of SEC61A1

• Sec61 is the key component of the mammalian co-translational protein translocation system and has been proposed to function as a two way channel that transports proteins both into the ER and back to the cytosol for degradation [5].
• In mammalian cells, the Sec61 complex and translocating chain-associated membrane protein (TRAM) are necessary and sufficient to direct the biogenesis, in the appropriate topology, of all secretory and membrane proteins examined thus far [6].
• We have addressed how ribosome-nascent chain complexes (RNCs), associated with the signal recognition particle (SRP), can be targeted to Sec61 translocation channels of the endoplasmic reticulum (ER) membrane when all binding sites are occupied by nontranslating ribosomes [7].
• It has been difficult, however, to discern the mechanistic principles of such disorders, in part, because membrane protein folding takes place coincident with translation and within a highly specialized environment formed by the ribosome, Sec61 translocon, and the ER membrane [8].

Anatomical context of SEC61A1

• Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction [9].
• Experiments using pancreatic microsomes revealed aberrant association of ribosomes and the Sec61 complex and enhanced ER stress in SERP1-/- pancreas [10].
• In basal conditions, the Sec61 complex in SERP1-/- microsomes was more cofractionated with ribosomes, compared with SERP1+/+ counterparts, in high-salt conditions [10].
• Secretion of newly synthesized proteins across the mammalian rough endoplasmic reticulum (translocation) is supported by the membrane proteins Sec61p and TRAM, but may also include accessory factors, depending on the particular translocation substrate [11].
• In the proteasome/TAP-dependent pathway, the translocon/Sec61 protein channel is an important element for the transport of antigenic peptides in phagosomes to the cytoplasm [12].

Associations of SEC61A1 with chemical compounds

• Conversely, treatment of cells with oleic acid, which increased the proportion of translocated apolipoprotein B, decreased the amount of ubiquitin-apolipoprotein B in the Sec61 complex [13].
• Treatment of cells with monomethylethanolamine or dithiothreitol decreased the translocation of apolipoprotein B and increased the proportion of ubiquitin-conjugated molecules associated with Sec61 [13].
• Before proteolysis of RI332, its N-linked oligosaccharide is cleaved in two distinct steps, the first of which might occur when the protein is still associated with the ER, as the trimmed glycoprotein intermediate efficiently interacts with calnexin and Sec61 [14].
• By UV-induced chemical cross-linking we further show that high cholesterol levels prevent cross-linking between ribosome-nascent chain complexes and components of the Sec61 translocon, but have no effect on cross-linking to the signal recognition particle [15].
• The TRAM protein (translocating chain-associating membrane protein) contacts the NH2-terminal region of the signal sequence while the mammalian Sec61p contacts the hydrophobic core of the signal sequence and regions COOH-terminal of this [16].

Physical interactions of SEC61A1

• Calnexin and other factors that alter translocation affect the rapid binding of ubiquitin to apoB in the Sec61 complex [13].
• Based on these results, we propose a model in which complex membrane proteins such as CFTR are transported through the Sec61 trimeric complex back to the cytosol, escorted by the beta subunit of Sec61, and degraded by the proteasome or by other proteolytic systems [5].
• At the ER membrane, the binding of the signal recognition particle (SRP) to its receptor triggers the release of SRP54 from its bound signal sequence and the nascent polypeptide is transferred to the Sec61 translocon for insertion into, or translocation across, the ER membrane [17].

Other interactions of SEC61A1

• During retrograde translocation from the ER to the cytosol, CFTR associates with the Sec61 trimeric complex [5].
• Accordingly, when ubiquitination is impaired, a considerable amount of RI332 binds to the ER chaperone calnexin and to the Sec61 complex that could effect retro-translocation of the polypeptide to the cytosol [14].
• The molecular mechanisms underlying BiP-mediated gating of the Sec61 translocon of the endoplasmic reticulum [18].
• Partial-length precursors were quantitatively isolated in a non-covalent, puromycin-sensitive complex (>3,500 kDa) that contained the Sec61 ER translocation machinery and the cytosolic chaperone Hsc70 [19].
• Our data raise the possibility that the Sec61 channel can be modified to accommodate a folded DHFR domain for dislocation, but not for translocation into the ER, or that a channel altogether distinct from Sec61 is used for dislocation [20].

Analytical, diagnostic and therapeutic context of SEC61A1

• On the basis of immunoprecipitation, this ER protein was shown to be identical to the recently identified mammalian Sec61 protein [21].
• Electron microscopy studies suggest that the channel may function as an oligomeric assembly of Sec61 or SecY complexes [22].

References