Editing Protein targeting (section)

==Protein translocation==<!-- Protein translocation redirects here -->
{{further|translocon}}Since the [[translation (biology)|translation]] of [[mRNA]] into protein by a [[ribosome]] takes place within the [[cytosol]], proteins destined for secretion or a specific [[organelle]] must be translocated.<ref>{{cite journal | vauthors = Sommer MS, Schleiff E | title = Protein targeting and transport as a necessary consequence of increased cellular complexity | journal = Cold Spring Harbor Perspectives in Biology | volume = 6 | issue = 8 | pages = a016055 | date = August 2014 | pmid = 25085907 | pmc = 4107987 | doi = 10.1101/cshperspect.a016055 }}</ref> This process can occur during translation, known as co-translational translocation, or after translation is complete, known as post-translational translocation.<ref>{{cite journal | vauthors = Walter P, Ibrahimi I, Blobel G | title = Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein | journal = The Journal of Cell Biology | volume = 91 | issue = 2 Pt 1 | pages = 545–50 | date = November 1981 | pmid = 7309795 | pmc = 2111968 | doi = 10.1083/jcb.91.2.545 }}</ref>

=== Co-translational translocation ===
[[File:General Overview of Protein Targeting.png|frame|A generalized overview of protein targeting that illustrates co-translational translocation to the endoplasmic reticulum and post-translational translocation to their specified locations. If no targeting sequence is present, then the synthesized protein will remain in the cytosol.]]
Most secretory and membrane-bound proteins are co-translationally translocated. Proteins that reside in the [[endoplasmic reticulum]] (ER), [[Golgi apparatus|golgi]] or [[endosome]]s also use the co-translational translocation pathway. This process begins while the protein is being synthesized on the ribosome, when a [[signal recognition particle]] (SRP) recognizes an N-terminal [[signal peptide]] of the nascent protein.<ref>{{cite journal | vauthors = Voorhees RM, Hegde RS | title = Toward a structural understanding of co-translational protein translocation | journal = Current Opinion in Cell Biology | volume = 41 | pages = 91–9 | date = August 2016 | pmid = 27155805 | doi = 10.1016/j.ceb.2016.04.009 }}</ref> Binding of the SRP temporarily pauses synthesis while the ribosome-protein complex is transferred to an [[SRP receptor]] on the ER in [[eukaryotes]], and the plasma membrane in [[prokaryotes]].<ref>{{cite journal | vauthors = Nyathi Y, Wilkinson BM, Pool MR | title = Co-translational targeting and translocation of proteins to the endoplasmic reticulum | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1833 | issue = 11 | pages = 2392–402 | date = November 2013 | pmid = 23481039 | doi = 10.1016/j.bbamcr.2013.02.021 | doi-access = free }}</ref> There, the nascent protein is inserted into the [[translocon]], a membrane-bound protein conducting channel composed of the [[Sec61|Sec61 translocation complex]] in eukaryotes, and the homologous [[Translocon#The prokaryotic translocon|SecYEG]] complex in prokaryotes.<ref>{{cite journal | vauthors = Mandon EC, Trueman SF, Gilmore R | title = Translocation of proteins through the Sec61 and SecYEG channels | journal = Current Opinion in Cell Biology | volume = 21 | issue = 4 | pages = 501–7 | date = August 2009 | pmid = 19450960 | doi = 10.1016/j.ceb.2009.04.010 | pmc = 2916700 }}</ref> In secretory proteins and type I [[transmembrane proteins]], the signal sequence is immediately cleaved from the nascent polypeptide once it has been translocated into the membrane of the ER (eukaryotes) or plasma membrane (prokaryotes) by [[signal peptidase]]. The signal sequence of type II membrane proteins and some polytopic membrane proteins are not cleaved off and therefore are referred to as signal anchor sequences. Within the ER, the protein is first covered by a [[Chaperone (protein)|chaperone protein]] to protect it from the high concentration of other proteins in the ER, giving it time to [[Protein folding|fold]] correctly.{{Citation needed|date=September 2024}} Once folded, the protein is modified as needed (for example, by [[glycosylation]]), then transported to the Golgi for further processing and goes to its target organelles or is retained in the ER by various [[ER retention]] mechanisms.

The amino acid chain of [[transmembrane proteins]], which often are [[transmembrane receptors]], passes through a membrane one or several times. These proteins are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor or signal-anchor sequence.<ref name="Alberts-2018">{{Cite book| vauthors = Alberts |url=https://www.worldcat.org/oclc/1048014962|title=Essential cell biology|date=November 2018|isbn=978-0-393-67953-3|edition=Fifth|location=New York|oclc=1048014962}}</ref> These complex membrane proteins are currently characterized using the same model of targeting that has been developed for secretory proteins. However, many complex multi-transmembrane proteins contain structural aspects that do not fit this model. Seven transmembrane G-protein coupled receptors (which represent about 5% of the genes in humans) mostly do not have an amino-terminal signal sequence. In contrast to secretory proteins, the first transmembrane domain acts as the first signal sequence, which targets them to the ER membrane. This also results in the translocation of the amino terminus of the protein into the ER membrane lumen. This translocation, which has been demonstrated with [[opsin]] with in vitro experiments,<ref>Kanner EM, Friedlander M, Simon SM. (2003). "Co-translational targeting and translocation of the amino terminus of opsin across the endoplasmic membrane requires GTP but not ATP". J. Biol. Chem. 278 (10): 7920–7926. {{doi|10.1074/jbc.M207462200}}. {{PMID|12486130}}.</ref><ref>Kanner EM, Klein IK. et al. (2002). "The amino terminus of opsin translocates "posttranslationally" as efficiently as cotranslationally". Biochemistry 41 (24): 7707–7715. {{doi|10.1021/bi0256882}}. {{PMID|12056902}}.</ref> breaks the usual pattern of "co-translational" translocation which has always held for mammalian proteins targeted to the ER. A great deal of the mechanics of transmembrane topology and folding remains to be elucidated.

===Post-translational translocation===
Even though most secretory proteins are co-translationally translocated, some are translated in the [[cytosol]] and later transported to the ER/plasma membrane by a post-translational system. In prokaryotes this process requires certain cofactors such as [[SecA]] and SecB and is facilitated by Sec62 and Sec63, two membrane-bound proteins.<ref>{{cite journal | vauthors = Rapoport TA | title = Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes | journal = Nature | volume = 450 | issue = 7170 | pages = 663–9 | date = November 2007 | pmid = 18046402 | doi = 10.1038/nature06384 | bibcode = 2007Natur.450..663R | s2cid = 2497138 }}</ref> The Sec63 complex, which is embedded in the ER membrane, causes hydrolysis of ATP, allowing chaperone proteins to bind to an exposed peptide chain and slide the polypeptide into the ER lumen. Once in the lumen the polypeptide chain can be folded properly. This process only occurs in unfolded proteins located in the cytosol.<ref name="Lodish-2008">{{cite book| vauthors = Lodish H, Berk A, Kaiser C, Krieger M, Bretscher A, Ploegh H, Amon A, Martin K |title=Molecular Cell Biology|date=2008|publisher=W.H. Freeman and Company|isbn=978-1-4641-8339-3|edition=8th|location=New York|pages=591–592}}</ref>

In addition, proteins targeted to other cellular destinations, such as [[mitochondria]], [[chloroplasts]], or [[peroxisomes]], use specialized post-translational pathways. Proteins targeted for the nucleus are also translocated post-translationally through the addition of a [[Nuclear localization signal|nuclear localization sequence]] (NLS) that promotes passage through the [[nuclear envelope]] via [[nuclear pore]]s.<ref>{{cite journal | vauthors = Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH | title = Classical nuclear localization signals: definition, function, and interaction with importin alpha | journal = The Journal of Biological Chemistry | volume = 282 | issue = 8 | pages = 5101–5 | date = February 2007 | pmid = 17170104 | pmc = 4502416 | doi = 10.1074/jbc.R600026200 | doi-access = free }}</ref>