translocon

{{main|Sec61}}

The translocon channel is a hetero-trimeric protein complex called SecYEG in prokaryotes and Sec61 in eukaryotes.{{cite encyclopedia | vauthors = Chang Z | chapter = Biogenesis of Secretory Proteins|date=2016-01-01 |encyclopedia=Encyclopedia of Cell Biology|pages=535–544| veditors = Bradshaw RA, Stahl PD |place=Waltham|publisher=Academic Press |language=en |doi=10.1016/b978-0-12-394447-4.10065-3 |isbn=978-0-12-394796-3 }} 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.{{cite journal | vauthors = Van den Berg B, Clemons WM, Collinson I, Modis Y, Hartmann E, Harrison SC, Rapoport TA | title = X-ray structure of a protein-conducting channel | journal = Nature | volume = 427 | issue = 6969 | pages = 36–44 | date = January 2004 | pmid = 14661030 | doi = 10.1038/nature02218 | s2cid = 4360143 | bibcode = 2004Natur.427...36B }} 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.{{Cite journal |last1=Meyer |first1=Hellmuth-Alexander |last2=Grau |first2=Harald |last3=Kraft |first3=Regine |last4=Kostka |first4=Susanne |last5=Prehn |first5=Siegfried |last6=Kalies |first6=Kai-Uwe |last7=Hartmann |first7=Enno |date=May 2000 |title=Mammalian Sec61 Is Associated with Sec62 and Sec63 |journal=Journal of Biological Chemistry |volume=275 |issue=19 |pages=14550–14557 |doi=10.1074/jbc.275.19.14550 |doi-access=free |pmid=10799540 |issn=0021-9258}} 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.

In bacteria, SecYEG forms a complex with SecDF, YajC and YidC.{{cite journal | vauthors = Duong F, Wickner W | title = Distinct catalytic roles of the SecYE, SecG and SecDFyajC subunits of preprotein translocase holoenzyme | journal = The EMBO Journal | volume = 16 | issue = 10 | pages = 2756–68 | date = May 1997 | pmid = 9184221 | pmc = 1169885 | doi = 10.1093/emboj/16.10.2756 }}{{cite journal | vauthors = Scotti PA, Urbanus ML, Brunner J, de Gier JW, von Heijne G, van der Does C, Driessen AJ, Oudega B, Luirink J | display-authors = 6 | title = YidC, the Escherichia coli homologue of mitochondrial Oxa1p, is a component of the Sec translocase | journal = The EMBO Journal | volume = 19 | issue = 4 | pages = 542–9 | date = February 2000 | pmid = 10675323 | pmc = 305592 | doi = 10.1093/emboj/19.4.542 }} 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.{{cite journal | vauthors = Pfeffer S, Dudek J, Gogala M, Schorr S, Linxweiler J, Lang S, Becker T, Beckmann R, Zimmermann R, Förster F | display-authors = 6 | title = Structure of the mammalian oligosaccharyl-transferase complex in the native ER protein translocon | journal = Nature Communications | volume = 5 | issue = 5 | pages = 3072 | year = 2014 | pmid = 24407213 | doi = 10.1038/ncomms4072 | doi-access = free | bibcode = 2014NatCo...5.3072P }}

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.{{cite journal | vauthors = Osborne AR, Rapoport TA, van den Berg B | title = Protein translocation by the Sec61/SecY channel | journal = Annual Review of Cell and Developmental Biology | volume = 21 | pages = 529–50 | date = 2005 | pmid = 16212506 | doi = 10.1146/annurev.cellbio.21.012704.133214 }}

File:OST PM-1.jpg

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.{{cite journal | vauthors = Simon SM, Blobel G | title = A protein-conducting channel in the endoplasmic reticulum | journal = Cell | volume = 65 | issue = 3 | pages = 371–80 | date = May 1991 | pmid = 1902142 | doi = 10.1016/0092-8674(91)90455-8 | s2cid = 33241198 }}{{cite journal | vauthors = Simon SM, Blobel G | title = Signal peptides open protein-conducting channels in E. coli | journal = Cell | volume = 69 | issue = 4 | pages = 677–84 | date = May 1992 | pmid = 1375130 | doi = 10.1016/0092-8674(92)90231-z | s2cid = 24540393 }}{{Cite journal |last1=Cross |first1=Benedict C. S. |last2=Sinning |first2=Irmgard |last3=Luirink |first3=Joen |last4=High |first4=Stephen |date=April 2009 |title=Delivering proteins for export from the cytosol |url=https://www.nature.com/articles/nrm2657 |journal=Nature Reviews Molecular Cell Biology |language=en |volume=10 |issue=4 |pages=255–264 |doi=10.1038/nrm2657 |pmid=19305415 |issn=1471-0080}}

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. Bacteria also use an SRP, together with a chaperone YidC that is similar to the eukaryote TRAM.{{cite journal | vauthors = Zhu L, Kaback HR, Dalbey RE | title = YidC protein, a molecular chaperone for LacY protein folding via the SecYEG protein machinery | journal = The Journal of Biological Chemistry | volume = 288 | issue = 39 | pages = 28180–94 | date = September 2013 | pmid = 23928306 | pmc = 3784728 | doi = 10.1074/jbc.M113.491613 | doi-access = free }}

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.

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.

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.{{cite journal | vauthors = Lycklama A, Nijeholt JA, Driessen AJ | title = The bacterial Sec-translocase: structure and mechanism | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 367 | issue = 1592 | pages = 1016–28 | date = April 2012 | pmid = 22411975 | pmc = 3297432 | doi = 10.1098/rstb.2011.0201 }} 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.

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.{{cite journal | vauthors = Römisch K | title = Surfing the Sec61 channel: bidirectional protein translocation across the ER membrane | journal = Journal of Cell Science | volume = 112 ( Pt 23) | issue = 23 | pages = 4185–91 | date = December 1999 | pmid = 10564637 | doi = 10.1242/jcs.112.23.4185 }} 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.{{cite journal | vauthors = Hampton RY, Sommer T | title = Finding the will and the way of ERAD substrate retrotranslocation | journal = Current Opinion in Cell Biology | volume = 24 | issue = 4 | pages = 460–6 | date = August 2012 | pmid = 22854296 | doi = 10.1016/j.ceb.2012.05.010 }}

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.{{Cite journal |last1=Crowder |first1=Justin J. |last2=Geigges |first2=Marco |last3=Gibson |first3=Ryan T. |last4=Fults |first4=Eric S. |last5=Buchanan |first5=Bryce W. |last6=Sachs |first6=Nadine |last7=Schink |first7=Andrea |last8=Kreft |first8=Stefan G. |last9=Rubenstein |first9=Eric M. |date=July 2015 |title=Rkr1/Ltn1 Ubiquitin Ligase-mediated Degradation of Translationally Stalled Endoplasmic Reticulum Proteins |journal=Journal of Biological Chemistry |language=en |volume=290 |issue=30 |pages=18454–18466 |doi=10.1074/jbc.M115.663559|doi-access=free |pmid=26055716 |pmc=4513105 }} Translocon clogging during post-translational translocation (PTT) may happen when proteins are not properly folded or form aggregates before they are fully translocated.{{Cite journal |last1=Ast |first1=Tslil |last2=Michaelis |first2=Susan |last3=Schuldiner |first3=Maya |date=January 2016 |title=The Protease Ste24 Clears Clogged Translocons |url=https://linkinghub.elsevier.com/retrieve/pii/S009286741501572X |journal=Cell |language=en |volume=164 |issue=1–2 |pages=103–114 |doi=10.1016/j.cell.2015.11.053|pmid=26771486 |pmc=4715265 }}{{Cite journal |last1=Runnebohm |first1=Avery M. |last2=Richards |first2=Kyle A. |last3=Irelan |first3=Courtney Broshar |last4=Turk |first4=Samantha M. |last5=Vitali |first5=Halie E. |last6=Indovina |first6=Christopher J. |last7=Rubenstein |first7=Eric M. |date=November 2020 |title=Overlapping function of Hrd1 and Ste24 in translocon quality control provides robust channel surveillance |journal=Journal of Biological Chemistry |language=en |volume=295 |issue=47 |pages=16113–16120 |doi=10.1074/jbc.AC120.016191|doi-access=free |pmid=33033070 |pmc=7681017 }}{{Cite journal |last1=Kayatekin |first1=Can |last2=Amasino |first2=Audra |last3=Gaglia |first3=Giorgio |last4=Flannick |first4=Jason |last5=Bonner |first5=Julia M. |last6=Fanning |first6=Saranna |last7=Narayan |first7=Priyanka |last8=Barrasa |first8=M. Inmaculada |last9=Pincus |first9=David |last10=Landgraf |first10=Dirk |last11=Nelson |first11=Justin |last12=Hesse |first12=William R. |last13=Costanzo |first13=Michael |last14=Myers |first14=Chad L. |last15=Boone |first15=Charles |date=March 2018 |title=Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity |url=https://linkinghub.elsevier.com/retrieve/pii/S0092867418301703 |journal=Cell |language=en |volume=173 |issue=1 |pages=62–73.e9 |doi=10.1016/j.cell.2018.02.026|pmc=5945206 }}

Translocon quality control mechanisms in the cell restore translocon function by relieving clogged translocon channels during protein translocation. 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.{{Cite journal |last1=Hiller |first1=Mark M. |last2=Finger |first2=Andreas |last3=Schweiger |first3=Markus |last4=Wolf |first4=Dieter H. |date=1996-09-20 |title=ER Degradation of a Misfolded Luminal Protein by the Cytosolic Ubiquitin-Proteasome Pathway |url=https://www.science.org/doi/10.1126/science.273.5282.1725 |journal=Science |volume=273 |issue=5282 |pages=1725–1728 |doi=10.1126/science.273.5282.1725|pmid=8781238 }}

• SecY protein
• Sec61
• Protein targeting
• Bacterial secretion system

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Category:Protein complexes

Category:Integral membrane proteins

Category:Protein targeting