Editing Signal peptide

{{Short description|Short peptide present at N-terminal of newly synthesized proteins}}
{{Infobox protein family
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| OPM family = 256
| OPM protein = 1skh
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A '''signal  peptide''' (sometimes referred to as '''signal sequence''', '''targeting signal''', '''localization signal''', '''localization sequence''', '''transit peptide''', '''leader sequence''' or '''leader peptide''') is a short [[peptide]] (usually 16–30 [[amino acid]]s long)<ref>{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK6322/|title=Post-Targeting Functions of Signal Peptides|last1=Kapp|first1=Katja|last2=Schrempf|first2=Sabrina|last3=Lemberg|first3=Marius K.|last4=Dobberstein|first4=Bernhard|date=2013-01-01|publisher=Landes Bioscience|language=en}}</ref> present at the [[N-terminal end|N-terminus]] (or occasionally nonclassically at the [[C-terminal end|C-terminus]]<ref name=":0">{{cite journal |last1=Owji |first1=Hajar |last2=Nezafat |first2=Navid |last3=Negahdaripour |first3=Manica |last4=Hajiebrahimi |first4=Ali |last5=Ghasemi |first5=Younes |title=A comprehensive review of signal peptides: Structure, roles, and applications |journal=European Journal of Cell Biology |date=August 2018 |volume=97 |issue=6 |pages=422–441 |doi=10.1016/j.ejcb.2018.06.003|pmid=29958716 |s2cid=49612506 }}</ref> or internally) of most newly synthesized [[proteins]] that are destined toward the [[secretory pathway]].<ref>{{cite journal | vauthors = Blobel G, Dobberstein B | title = Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma | journal = The Journal of Cell Biology | volume = 67 | issue = 3 | pages = 835–51 | date = December 1975 | pmid = 811671 | pmc = 2111658 | doi = 10.1083/jcb.67.3.835 }}</ref>
These proteins include those that reside either inside certain organelles (the [[endoplasmic reticulum]], [[golgi apparatus|Golgi]] or [[endosomes]]), secreted from the cell, or inserted into most cellular membranes. Although most [[Transmembrane protein#Classification by Topology|type I]] [[Transmembrane protein|membrane-bound proteins]] have signal peptides, most [[Transmembrane protein#Classification by Topology|type II]] and multi-spanning membrane-bound proteins are targeted to the secretory pathway by their first [[transmembrane domain]], which biochemically resembles a signal sequence except that it is not cleaved. They are a kind of [[target peptide]].

==Function (translocation)==
Signal peptides function to prompt a cell to [[Protein targeting#Protein translocation|translocate]] the protein, usually to the cellular membrane. In [[prokaryotes]], signal peptides direct the newly synthesized protein to the SecYEG protein-conducting channel, which is present in the [[plasma membrane]]. A homologous system exists in [[eukaryotes]], where the signal peptide directs the newly synthesized protein to the Sec61 channel, which shares structural and sequence homology with SecYEG, but is present in the endoplasmic reticulum.<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> Both the SecYEG and Sec61 channels are commonly referred to as the [[translocon]], and transit through this channel is known as translocation. While secreted proteins are threaded through the channel, transmembrane domains may diffuse across a lateral gate in the translocon to partition into the surrounding membrane.

==Structure==
The core of the signal peptide contains a long stretch of hydrophobic amino acids (about 5–16 residues long)<ref>{{cite journal | vauthors = Käll L, Krogh A, Sonnhammer EL | title = A combined transmembrane topology and signal peptide prediction method | journal = Journal of Molecular Biology | volume = 338 | issue = 5 | pages = 1027–36 | date = May 2004 | pmid = 15111065 | doi = 10.1016/j.jmb.2004.03.016 }}</ref> that has a tendency to form a single alpha-helix and is also referred to as the "h-region". In addition, many signal peptides begin with a short positively charged stretch of amino acids, which may help to enforce proper topology of the polypeptide during translocation by what is known as the '''positive-inside rule'''.<ref name="von Heijne-1988">{{cite journal | vauthors = von Heijne G, Gavel Y | title = Topogenic signals in integral membrane proteins | journal = European Journal of Biochemistry | volume = 174 | issue = 4 | pages = 671–8 | date = July 1988 | pmid = 3134198 | doi = 10.1111/j.1432-1033.1988.tb14150.x | doi-access = free | author-link1 = Gunnar von Heijne }}</ref> Because of its close location to the [[N-terminus]] it is called the "n-region". At the end of the signal peptide there is typically a stretch of amino acids that is recognized and cleaved by [[signal peptidase]] and therefore named cleavage site. This cleavage site is absent from transmembrane-domains that serve as signal peptides, which are sometimes referred to as signal anchor sequences. Signal peptidase may cleave either during or after completion of translocation to generate a free signal peptide and a mature protein. The free signal peptides are then digested by specific proteases.
Moreover, different target locations are aimed by different types of signal peptides. For example, the structure of a target peptide aiming for the mitochondrial environment differs in terms of length and shows an alternating pattern of small positively charged and hydrophobic stretches. Nucleus aiming signal peptides can be found at both the N-terminus and the C-terminus of a protein and are in most cases retained in the mature protein.

==Co-translational versus post-translational translocation==
In both prokaryotes and eukaryotes signal sequences may act co-translationally or post-translationally.

The co-translational pathway is initiated when the signal peptide emerges from the [[ribosome]] and is recognized by the [[signal-recognition particle]] (SRP).<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> SRP then halts further translation (translational arrest only occurs in Eukaryotes) and directs the signal sequence-ribosome-mRNA complex to the [[SRP receptor]], which is present on the surface of either the plasma membrane (in prokaryotes) or the ER (in eukaryotes).<ref>{{cite journal | vauthors = Gilmore R, Blobel G, Walter P | title = Protein translocation across the endoplasmic reticulum. I. Detection in the microsomal membrane of a receptor for the signal recognition particle | journal = The Journal of Cell Biology | volume = 95 | issue = 2 Pt 1 | pages = 463–9 | date = November 1982 | pmid = 6292235 | pmc = 2112970 | doi = 10.1083/jcb.95.2.463 }}</ref> Once membrane-targeting is completed, the signal sequence is inserted into the translocon. Ribosomes are then physically docked onto the cytoplasmic face of the translocon and protein synthesis resumes.<ref>{{cite journal | vauthors = Görlich D, Prehn S, Hartmann E, Kalies KU, Rapoport TA | title = A mammalian homolog of SEC61p and SECYp is associated with ribosomes and nascent polypeptides during translocation | journal = Cell | volume = 71 | issue = 3 | pages = 489–503 | date = October 1992 | pmid = 1423609 | doi = 10.1016/0092-8674(92)90517-G | s2cid = 19078317 }}</ref>

The post-translational pathway is initiated after protein synthesis is completed. In prokaryotes, the signal sequence of post-translational substrates is recognized by the [[SecB]] [[chaperone protein]] that transfers the protein to the [[SecA]] ATPase, which in turn pumps the protein through the translocon. Although post-translational translocation is known to occur in eukaryotes, it is poorly understood. It is known that in yeast post-translational translocation requires the translocon and two additional membrane-bound proteins, [[TLOC1|Sec62]] and [[SEC63|Sec63]].<ref name="Panzner1995">{{cite journal | vauthors = Panzner S, Dreier L, Hartmann E, Kostka S, Rapoport TA | title = Posttranslational protein transport in yeast reconstituted with a purified complex of Sec proteins and Kar2p | journal = Cell | volume = 81 | issue = 4 | pages = 561–70 | date = May 1995 | pmid = 7758110 | doi = 10.1016/0092-8674(95)90077-2 | s2cid = 14398668 | doi-access = free }}</ref>

==Secretion efficiency determination==

Signal peptides are extremely heterogeneous, many prokaryotic and eukaryotic ones are functionally interchangeable within or between species and all determine protein secretion efficiency.<ref name="pmid23124363">{{cite journal | vauthors = Kober L, Zehe C, Bode J | title = Optimized signal peptides for the development of high expressing CHO cell lines | journal = Biotechnology and Bioengineering | volume = 110 | issue = 4 | pages = 1164–73 | date = April 2013 | pmid = 23124363 | doi = 10.1002/bit.24776 | s2cid = 449870 }}</ref><ref name="pmid4032478">{{cite journal | vauthors = von Heijne G | title = Signal sequences. The limits of variation | journal = Journal of Molecular Biology | volume = 184 | issue = 1 | pages = 99–105 | date = July 1985 | pmid = 4032478 | doi = 10.1016/0022-2836(85)90046-4 | author-link = Gunnar von Heijne }}</ref><ref>{{cite journal | vauthors = Molino JV, de Carvalho JC, Mayfield SP | title = Comparison of secretory signal peptides for heterologous protein expression in microalgae: Expanding the secretion portfolio for Chlamydomonas reinhardtii | journal = PLOS ONE | volume = 13 | issue = 2 | pages = e0192433 | date = 2018-02-06 | pmid = 29408937 | pmc = 5800701 | doi = 10.1371/journal.pone.0192433 | bibcode = 2018PLoSO..1392433M | doi-access = free }}</ref>

==Nucleotide level features==

In vertebrates, the region of the [[mRNA]] that codes for the signal peptide (i.e. the signal sequence coding region, or SSCR) can function as an RNA element with specific activities. SSCRs promote nuclear mRNA export and the proper localization to the surface of the endoplasmic reticulum. In addition SSCRs have specific sequence features: they have low [[adenine]]-content, are enriched in certain [[sequence motif|motifs]], and tend to be present in the first [[exon]] at a frequency that is higher than expected.<ref name="PalazzoSpringer2007">{{cite journal | vauthors = Palazzo AF, Springer M, Shibata Y, Lee CS, Dias AP, Rapoport TA | title = The signal sequence coding region promotes nuclear export of mRNA | journal = PLOS Biology | volume = 5 | issue = 12 | pages = e322 | date = December 2007 | pmid = 18052610 | pmc = 2100149 | doi = 10.1371/journal.pbio.0050322 | doi-access = free }}</ref><ref name="Cenik2011">{{cite journal | vauthors = Cenik C, Chua HN, Zhang H, Tarnawsky SP, Akef A, Derti A, Tasan M, Moore MJ, Palazzo AF, Roth FP | display-authors = 6 | title = Genome analysis reveals interplay between 5'UTR introns and nuclear mRNA export for secretory and mitochondrial genes | journal = PLOS Genetics | volume = 7 | issue = 4 | pages = e1001366 | date = April 2011 | pmid = 21533221 | pmc = 3077370 | doi = 10.1371/journal.pgen.1001366 | editor1-last = Snyder | editor1-first = Michael | doi-access = free }}</ref>

==Alternate secretion mechanisms==
Proteins without signal peptides can also be secreted by unconventional mechanisms. E.g. Interleukin, Galectin.<ref>{{cite journal | vauthors = Nickel W, Seedorf M | title = Unconventional mechanisms of protein transport to the cell surface of eukaryotic cells | journal = Annual Review of Cell and Developmental Biology | volume = 24 | pages = 287–308 | date = 2008 | pmid = 18590485 | doi = 10.1146/annurev.cellbio.24.110707.175320 }}</ref> The process by which such secretory proteins gain access to the cell exterior is termed [[unconventional protein secretion]] (UPS). In plants, even 50% of secreted proteins can be UPS dependent.<ref>{{cite journal | vauthors = Agrawal GK, Jwa NS, Lebrun MH, Job D, Rakwal R | title = Plant secretome: unlocking secrets of the secreted proteins | journal = Proteomics | volume = 10 | issue = 4 | pages = 799–827 | date = February 2010 | pmid = 19953550 | doi = 10.1002/pmic.200900514 | s2cid = 20647387 }}</ref>

==Nonclassical sequences==
Signal peptides are usually located at the N-terminus of proteins. Some have C-terminal or internal signal peptides (examples: peroxisomal targeting signal and nuclear localisation signal). The structure of these nonclassical signal peptides differs vastly from the N-terminal signal peptides.<ref name=":0" />

==Nomenclature==
Signal peptides are not to be confused with the leader peptides sometimes encoded by leader mRNA, although both are sometimes ambiguously referred to as "leader peptides." These other leader peptides are short polypeptides that do not function in protein localization, but instead may regulate transcription or translation of the main protein, and are not part of the final protein sequence. This type of leader peptide primarily refers to a form of gene regulation found in bacteria, although a similar mechanism is used to regulate eukaryotic genes, which is referred to as uORFs (upstream open reading frames).

== Signal peptide as a therapeutic target ==
Signal peptide is a potential (therapeutic) [[Antiviral drug|antiviral]] target. Signal peptides with penultimate N-terminus glycine is a target for [[IMP-1088|NMT inhibitors]], which inhibit the [[myristoylation]] of signal peptides and target the signal peptide for [[Proteasome|degradation]], which affects virus-cellular [[Fusion mechanism|fusion]]. <ref>{{Cite journal |last1=Witwit |first1=Haydar |last2=Betancourt |first2=Carlos Alberto |last3=Cubitt |first3=Beatrice |last4=Khafaji |first4=Roaa |last5=Kowalski |first5=Heinrich |last6=Jackson |first6=Nathaniel |last7=Ye |first7=Chengjin |last8=Martinez-Sobrido |first8=Luis |last9=de la Torre |first9=Juan C. |date=2024-08-26 |title=Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication |journal=Viruses |language=en |volume=16 |issue=9 |pages=1362 |doi=10.3390/v16091362 |doi-access=free |issn=1999-4915|pmc=11436053 }}</ref>

== See also ==
* [[Protein targeting]]
* [[Target peptide]]
* [[Topogenic sequence]]

== References ==
<references />

== External links ==
* {{MeshName|Signal+Peptide}}
* [http://proline.bic.nus.edu.sg/spdb/ SPdb (Signal Peptide DataBase)] {{Webarchive|url=https://web.archive.org/web/20160122133309/http://proline.bic.nus.edu.sg/spdb/ |date=2016-01-22 }}
* [https://services.healthtech.dtu.dk/services/SignalP-6.0/ SignalP] — predicts the presence and location of signal peptide cleavage sites in amino acid sequences from different organisms.

{{Posttranslational modification}}

{{DEFAULTSORT:Signal Peptide}}
[[Category:Gene expression]]
[[Category:Protein targeting]]