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Translocon

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The translocon (also known as a translocator or translocation channel) is a complex of proteins associated with the translocation of polypeptides across membranes.[1] In eukaryotes the term translocon most commonly refers to the complex that transports nascent polypeptides with a targeting signal sequence into the interior (cisternal or lumenal) space of the endoplasmic reticulum (ER) from the cytosol. This translocation process requires the protein to cross a hydrophobic lipid bilayer. The same complex is also used to integrate nascent proteins into the membrane itself (membrane proteins). In prokaryotes, a similar protein complex transports polypeptides across the (inner) plasma membrane or integrates membrane proteins.[2] In either case, the protein complex is formed from Sec proteins (Sec: secretory), with the hetero-trimeric Sec61 being the channel.[3] In prokaryotes, the homologous channel complex is known as SecYEG.[4]

This article focuses on the cell's native translocons, but pathogens can also assemble other translocons in their host membranes, allowing them to export virulence factors into their target cells.[5]

Central channel

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Main article: Sec61

The translocon channel is a hetero-trimeric protein complex called SecYEG in prokaryotes and Sec61 in eukaryotes.[6] It consists of the subunits SecY, SecE, and SecG. The structure of this channel, in its idle state, has been solved by X-ray crystallography in archaea.[4] SecY is the large pore subunit. A larger heptameric complex that includes the core trimeric protein and a tetramer is responsible for the transportation of a subset of polypeptides into the endoplasmic reticulum.[7] The distinct features of the channel contribute to its function in the ER membrane. In a side view, the channel has an hourglass shape, with a funnel on each side. The extracellular funnel has a little "plug" formed out of an alpha-helix. In the middle of the membrane is a construction, formed from a pore ring of six hydrophobic amino acids that project their side chains inwards. This ensures selectivity of elements entering the channel. During protein translocation, the plug is moved out of the way, and a polypeptide chain is moved from the cytoplasmic funnel, through the pore ring, the extracellular funnel, into the extracellular space. Hydrophobic segments of membrane proteins exit sideways through the lateral gate into the lipid phase and become membrane-spanning segments.[4]

In bacteria, SecYEG forms a complex with SecDF, YajC and YidC.[8][9] In eukaryotes, Sec61 forms a complex with the oligosaccharyl transferase complex, the TRAP complex, and the membrane protein TRAM (possible chaperone). For further components, such as signal peptidase complex and the SRP receptor it is not clear to what extent they only associate transiently to the translocon complex.[10]

Translocation

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The channel allows peptides to move in either direction, so additional systems in the translocon are required to move the peptide in a specific direction. There are two types of translocation: co-translational translocation (occurs concurrently with translation), and post-translational translocation (happens after translation). Each is seen in eukaryotes and bacteria. While eukaryotes unfold the protein with BiP and use other complexes to transport the peptide, bacteria use the SecA ATPase.[11]

Co-translational translocation (CTT)

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ER translocon complex. Many protein complexes are involved in protein synthesis. The actual production takes place in the ribosomes (yellow and light blue). Through the ER translocon (green: Sec61, blue: TRAP complex, and red: oligosaccharyl transferase complex) the newly synthesized protein is transported across the membrane (gray) into the interior of the ER. Sec61 is the protein-conducting channel and the OST adds sugar moieties to the nascent protein.

In co-translational translocation, the translocon associates with the ribosome so that a growing nascent polypeptide chain is moved from the ribosome tunnel into the translocon channel. The co-translational translocation process in eukaryotes involves SRP that guide nascent polypeptide chains to the translocon while they are still associated with the ribosome. The translocon (translocator) acts as a channel through the hydrophobic membrane of the endoplasmic reticulum (after the SRP has dissociated and translation is continued). The emerging polypeptide is threaded through the channel as an unfolded string of amino acids, potentially driven by a Brownian Ratchet. Once translation has been completed, a signal peptidase cleaves off the short signal peptide from the nascent protein, leaving the polypeptide free in the interior of the endoplasmic reticulum.[12][13][14]

In eukaryotes, proteins due to be translocated to the endoplasmic reticulum are recognized by the signal-recognition particle (SRP), which halts translation of the polypeptide by the ribosome while it attaches the ribosome to the SRP receptor on the endoplasmic reticulum. This recognition event is based upon a specific N-terminal signal sequence that is in the first few codons of the polypeptide to be synthesised.[11] Bacteria also use an SRP, together with a chaperone YidC that is similar to the eukaryote TRAM.[15][11]

The translocon can also translocate and integrate membrane proteins in the correct orientation into the membrane of the endoplasmic reticulum. The mechanism of this process is not fully understood but involves the recognition and processing by the translocon of hydrophobic stretches in the amino acid sequence, which are destined to become transmembrane helices. Closed by stop-transfer sequences and opened by embedded signal sequences, the plug alters between its open and closed states to place helices in different orientations.[11]

Post-translational translocation (PTT)

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In eukaryotes, post-translational translocation depends on BiP and other complexes, including the SEC62/SEC63 integral membrane protein complex. In this mode of translocation, Sec63 helps BiP hydrolyze ATP, which then binds to the peptide and "pulls" it out. This process is repeated for other BiP molecules until the entire peptide has been pulled through.[11]

In bacteria, the same process is done by a "pushing" ATPase known as SecA, sometimes assisted by the SecDF complex on the other side responsible for pulling.[16] The SecA ATPase uses a "push-and-slide" mechanism to move a polypeptide through the channel. In the ATP-bound state, SecA interacts through a two-helix finger with a subset of amino acids in a substrate, pushing them (with ATP hydrolysis) into the channel. The interaction is then weakened as SecA enters the ADP-bound state, allowing the polypeptide chain to slide passively in either direction. SecA then grabs a further section of the peptide to repeat the process.[11]

The ER-retrotranslocon

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Translocators can also move polypeptides (such as damaged proteins targeted for proteasomes) from the cisternal space of the endoplasmic reticulum to the cytosol. ER-proteins are degraded in the cytosol by the 26S proteasome, a process known as endoplasmic-reticulum-associated protein degradation, and therefore have to be transported by an appropriate channel. This retrotranslocon is still enigmatic.

It was initially believed that the Sec61 channel is responsible for this retrograde transport, implying that transport through Sec61 is not always unidirectional but also can be bidirectional.[17] However, the structure of Sec61 does not support this view and several different proteins have been suggested to be responsible for transport from the ER lumen into the cytosol.[18]

Translocon Quality Control (TQC)

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Translocons can be clogged by translationally stalled or improperly folded proteins engaging with the complex. This is one of the ways translocons can become dysfunctional; for example in co-translational translocation (CTT), translocon clogging can occur due to translationally stalled ER-targeted proteins.[19] Translocon clogging during post-translational translocation (PTT) may happen when proteins are not properly folded or form aggregates before they are fully translocated.[20][21][22]

Translocon quality control mechanisms in the cell restore translocon function by relieving clogged translocon channels during protein translocation.[21] The Ubiquitin proteasome system (UPS) is one of multiple degradation mechanisms under TQC. The process includes clogged protein targeting by the attachment of Ubiquitin enzymes for degradation by the proteasome.[23]


See Also

References

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  1. ^ Johnson AE, van Waes MA (1999). "The translocon: a dynamic gateway at the ER membrane". Annual Review of Cell and Developmental Biology. 15: 799–842. doi:10.1146/annurev.cellbio.15.1.799. PMID 10611978.
  2. ^ Gold VA, Duong F, Collinson I (2007). "Structure and function of the bacterial Sec translocon". Molecular Membrane Biology. 24 (5–6): 387–94. doi:10.1080/09687680701416570. PMID 17710643. S2CID 83946219.
  3. ^ Deshaies RJ, Sanders SL, Feldheim DA, Schekman R (February 1991). "Assembly of yeast Sec proteins involved in translocation into the endoplasmic reticulum into a membrane-bound multisubunit complex". Nature. 349 (6312): 806–8. Bibcode:1991Natur.349..806D. doi:10.1038/349806a0. PMID 2000150. S2CID 31383053.
  4. ^ a b c Van den Berg B, Clemons WM, Collinson I, Modis Y, Hartmann E, Harrison SC, Rapoport TA (January 2004). "X-ray structure of a protein-conducting channel". Nature. 427 (6969): 36–44. Bibcode:2004Natur.427...36B. doi:10.1038/nature02218. PMID 14661030. S2CID 4360143.
  5. ^ Mueller CA, Broz P, Cornelis GR (June 2008). "The type III secretion system tip complex and translocon". Molecular Microbiology. 68 (5): 1085–95. doi:10.1111/j.1365-2958.2008.06237.x. PMID 18430138. S2CID 205366024.
  6. ^ Chang Z (2016-01-01). "Biogenesis of Secretory Proteins". In Bradshaw RA, Stahl PD (eds.). Encyclopedia of Cell Biology. Waltham: Academic Press. pp. 535–544. doi:10.1016/b978-0-12-394447-4.10065-3. ISBN 978-0-12-394796-3.
  7. ^ Meyer, Hellmuth-Alexander; Grau, Harald; Kraft, Regine; Kostka, Susanne; Prehn, Siegfried; Kalies, Kai-Uwe; Hartmann, Enno (May 2000). "Mammalian Sec61 Is Associated with Sec62 and Sec63". Journal of Biological Chemistry. 275 (19): 14550–14557. doi:10.1074/jbc.275.19.14550. ISSN 0021-9258. PMID 10799540.
  8. ^ Duong F, Wickner W (May 1997). "Distinct catalytic roles of the SecYE, SecG and SecDFyajC subunits of preprotein translocase holoenzyme". The EMBO Journal. 16 (10): 2756–68. doi:10.1093/emboj/16.10.2756. PMC 1169885. PMID 9184221.
  9. ^ Scotti PA, Urbanus ML, Brunner J, de Gier JW, von Heijne G, van der Does C, et al. (February 2000). "YidC, the Escherichia coli homologue of mitochondrial Oxa1p, is a component of the Sec translocase". The EMBO Journal. 19 (4): 542–9. doi:10.1093/emboj/19.4.542. PMC 305592. PMID 10675323.
  10. ^ Pfeffer S, Dudek J, Gogala M, Schorr S, Linxweiler J, Lang S, et al. (2014). "Structure of the mammalian oligosaccharyl-transferase complex in the native ER protein translocon". Nature Communications. 5 (5): 3072. Bibcode:2014NatCo...5.3072P. doi:10.1038/ncomms4072. PMID 24407213.
  11. ^ a b c d e f Osborne AR, Rapoport TA, van den Berg B (2005). "Protein translocation by the Sec61/SecY channel". Annual Review of Cell and Developmental Biology. 21: 529–50. doi:10.1146/annurev.cellbio.21.012704.133214. PMID 16212506.
  12. ^ Simon SM, Blobel G (May 1991). "A protein-conducting channel in the endoplasmic reticulum". Cell. 65 (3): 371–80. doi:10.1016/0092-8674(91)90455-8. PMID 1902142. S2CID 33241198.
  13. ^ Simon SM, Blobel G (May 1992). "Signal peptides open protein-conducting channels in E. coli". Cell. 69 (4): 677–84. doi:10.1016/0092-8674(92)90231-z. PMID 1375130. S2CID 24540393.
  14. ^ Cross, Benedict C. S.; Sinning, Irmgard; Luirink, Joen; High, Stephen (April 2009). "Delivering proteins for export from the cytosol". Nature Reviews Molecular Cell Biology. 10 (4): 255–264. doi:10.1038/nrm2657. ISSN 1471-0080. PMID 19305415.
  15. ^ Zhu L, Kaback HR, Dalbey RE (September 2013). "YidC protein, a molecular chaperone for LacY protein folding via the SecYEG protein machinery". The Journal of Biological Chemistry. 288 (39): 28180–94. doi:10.1074/jbc.M113.491613. PMC 3784728. PMID 23928306.
  16. ^ Lycklama A, Nijeholt JA, Driessen AJ (April 2012). "The bacterial Sec-translocase: structure and mechanism". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 367 (1592): 1016–28. doi:10.1098/rstb.2011.0201. PMC 3297432. PMID 22411975.
  17. ^ Römisch K (December 1999). "Surfing the Sec61 channel: bidirectional protein translocation across the ER membrane". Journal of Cell Science. 112 ( Pt 23) (23): 4185–91. doi:10.1242/jcs.112.23.4185. PMID 10564637.
  18. ^ Hampton RY, Sommer T (August 2012). "Finding the will and the way of ERAD substrate retrotranslocation". Current Opinion in Cell Biology. 24 (4): 460–6. doi:10.1016/j.ceb.2012.05.010. PMID 22854296.
  19. ^ Crowder, Justin J.; Geigges, Marco; Gibson, Ryan T.; Fults, Eric S.; Buchanan, Bryce W.; Sachs, Nadine; Schink, Andrea; Kreft, Stefan G.; Rubenstein, Eric M. (July 2015). "Rkr1/Ltn1 Ubiquitin Ligase-mediated Degradation of Translationally Stalled Endoplasmic Reticulum Proteins". Journal of Biological Chemistry. 290 (30): 18454–18466. doi:10.1074/jbc.M115.663559. PMC 4513105. PMID 26055716.
  20. ^ Ast, Tslil; Michaelis, Susan; Schuldiner, Maya (January 2016). "The Protease Ste24 Clears Clogged Translocons". Cell. 164 (1–2): 103–114. doi:10.1016/j.cell.2015.11.053. PMID 26771486.
  21. ^ a b Runnebohm, Avery M.; Richards, Kyle A.; Irelan, Courtney Broshar; Turk, Samantha M.; Vitali, Halie E.; Indovina, Christopher J.; Rubenstein, Eric M. (November 2020). "Overlapping function of Hrd1 and Ste24 in translocon quality control provides robust channel surveillance". Journal of Biological Chemistry. 295 (47): 16113–16120. doi:10.1074/jbc.AC120.016191. PMID 33033070.
  22. ^ Kayatekin, Can; Amasino, Audra; Gaglia, Giorgio; Flannick, Jason; Bonner, Julia M.; Fanning, Saranna; Narayan, Priyanka; Barrasa, M. Inmaculada; Pincus, David; Landgraf, Dirk; Nelson, Justin; Hesse, William R.; Costanzo, Michael; Myers, Chad L.; Boone, Charles (March 2018). "Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity". Cell. 173 (1): 62–73.e9. doi:10.1016/j.cell.2018.02.026.
  23. ^ Hiller, Mark M.; Finger, Andreas; Schweiger, Markus; Wolf, Dieter H. (1996-09-20). "ER Degradation of a Misfolded Luminal Protein by the Cytosolic Ubiquitin-Proteasome Pathway". Science. 273 (5282): 1725–1728. doi:10.1126/science.273.5282.1725. PMID 8781238.
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