Signal Peptide
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Signal Peptide

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 acids long)[1] present at the N-terminus of the majority of newly synthesized proteins that are destined towards the secretory pathway.[2] These proteins include those that reside either inside certain organelles (the endoplasmic reticulum, Golgi or endosomes), secreted from the cell, or inserted into most cellular membranes. Although most type I membrane-bound proteins have signal peptides, the majority of 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 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.[3] 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.

Signal peptide structure

The core of the signal peptide contains a long stretch of hydrophobic amino acids (about 5-16 residues long)[4] 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.[5] 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. However 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 the majority of the cases retained in the mature protein.

It is possible to determine the amino acid sequence of the N-terminal signal peptide by Edman degradation, a cyclic procedure that cleaves off the amino acids one at a time.[6][7]

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).[8] 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).[9] 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.[10]

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 however known that in yeast post-translational translocation requires the translocon and two additional membrane-bound proteins, Sec62 and Sec63.[11]

Signal peptides determine secretion efficiency

Signal peptides are extremely heterogeneous and many prokaryotic and eukaryotic signal peptides are functionally interchangeable even between different species however the efficiency of protein secretion is strongly determined by the signal peptide.[12][13]

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 motifs, and tend to be present in the first exon at a frequency that is higher than expected.[14][15]

Signal peptide less secretion

Proteins without signal peptides can also be secreted by unconventional mechanisms. E.g. Interleukin, Galectin.[16] 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.[17]

See also


  1. ^ Kapp, Katja; Schrempf, Sabrina; Lemberg, Marius K.; Dobberstein, Bernhard (2013-01-01). Post-Targeting Functions of Signal Peptides. Landes Bioscience.
  2. ^ Blobel G, Dobberstein B (Dec 1975). "Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma". Journal of Cell Biology. 67 (3): 835-51. doi:10.1083/jcb.67.3.835. PMC 2111658. PMID 811671.
  3. ^ Rapoport T. (Nov 2007). "Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes". Nature. 450 (7170): 663-9. doi:10.1038/nature06384. PMID 18046402.
  4. ^ Käll, Lukas; Krogh, Anders; Sonnhammer, Erik L. L. (2004). "A Combined Transmembrane Topology and Signal Peptide Prediction Method". J. Mol. Biol. 338 (5): 1027-1036. doi:10.1016/j.jmb.2004.03.016. PMID 15111065.
  5. ^ von Heijne, G.; Gavel, Y. (Jul 1988). "Topogenic signals in integral membrane proteins". Eur J Biochem. 174 (4): 671-8. doi:10.1111/j.1432-1033.1988.tb14150.x. PMID 3134198.
  6. ^ "26.6 Peptide Sequencing: The Edman Degradation". Chemistry LibreTexts. 2015-08-26. Retrieved .
  7. ^ "N-terminal sequencing service - Edman degradation". Retrieved .
  8. ^ Walter P, Ibrahimi I, Blobel G (Nov 1981). "Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein". Journal of Cell Biology. 91 (2 Pt1): 545-50. doi:10.1083/jcb.91.2.545. PMC 2111968. PMID 7309795.
  9. ^ Gilmore R, Blobel G, Walter P (Nov 1982). "Protein translocation across the endoplasmic reticulum. I. Detection in the microsomal membrane of a receptor for the signal recognition particle". Journal of Cell Biology. 95 (2 Pt1): 463-9. doi:10.1083/jcb.95.2.463. PMC 2112970. PMID 6292235.
  10. ^ Görlich D, Prehn S, Hartmann E, Kalies KU, Rapoport TA (Oct 1992). "A mammalian homolog of SEC61p and SECYp is associated with ribosomes and nascent polypeptides during translocation". Cell. 71 (3): 489-503. doi:10.1016/0092-8674(92)90517-G. PMID 1423609.
  11. ^ Panzner, S; Dreier, L; Hartmann, E; Kostka, S; Rapoport, TA (1995). "Posttranslational protein transport in yeast reconstituted with a purified complex of Sec proteins and Kar2p". Cell. 81 (4): 561-570. doi:10.1016/0092-8674(95)90077-2. ISSN 0092-8674. PMID 7758110.
  12. ^ Kober L, Zehe C, Bode J (April 2013). "Optimized signal peptides for the development of high expressing CHO cell lines". Biotechnol. Bioeng. 110 (4): 1164-73. doi:10.1002/bit.24776. PMID 23124363.
  13. ^ von Heijne G (Jul 1985). "Signal sequences: The limits of variation". J Mol Biol. 184 (1): 99-105. doi:10.1016/0022-2836(85)90046-4. PMID 4032478.
  14. ^ Palazzo, Alexander F.; Springer, Michael; Shibata, Yoko; Lee, Chung-Sheng; Dias, Anusha P.; Rapoport, Tom A. (2007). "The Signal Sequence Coding Region Promotes Nuclear Export of mRNA". PLoS Biology. 5 (12): e322. doi:10.1371/journal.pbio.0050322. ISSN 1544-9173. PMC 2100149. PMID 18052610.
  15. ^ Cenik, Can; Chua, Hon Nian; Zhang, Hui; Tarnawsky, Stefan P.; Akef, Abdalla; Derti, Adnan; Tasan, Murat; Moore, Melissa J.; Palazzo, Alexander F.; Roth, Frederick P. (2011). Snyder, Michael (ed.). "Genome Analysis Reveals Interplay between 5?UTR Introns and Nuclear mRNA Export for Secretory and Mitochondrial Genes". PLoS Genetics. 7 (4): e1001366. doi:10.1371/journal.pgen.1001366. ISSN 1553-7404. PMC 3077370. PMID 21533221.
  16. ^ Nickel, W; Seedorf, M (2008). "Unconventional mechanisms of protein transport to the cell surface of eukaryotic cells". Annual Review of Cell and Developmental Biology. 24: 287-308. doi:10.1146/annurev.cellbio.24.110707.175320. PMID 18590485.
  17. ^ Agrawal, GK; Jwa, NS; Lebrun, MH; Job, D; Rakwal, R (February 2010). "Plant secretome: unlocking secrets of the secreted proteins". Proteomics. 10 (4): 799-827. doi:10.1002/pmic.200900514. PMID 19953550.

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