A signal peptide is a short peptide present at the N-terminus of the majority of newly
synthesized proteins that are destined towards the secretory pathway. These proteins include
those that reside either inside certain organelles, 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.
Translocation 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. 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 that
has a tendency to form a single alpha-helix. 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.
At the end of the signal peptide there is typically a stretch of amino acids that is
recognized and cleaved by signal peptidase. 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. 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 then halts further translation and directs the signal sequence-ribosome-mRNA
complex to the SRP receptor, which is present on the surface of either the plasma membrane
or the ER. 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. 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 turns 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. 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.
Nucleotide level features In vertebrates, the region of the mRNA that
codes for the signal peptide 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. See also
Protein targeting Target peptide
Topogenic sequence References
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processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of
murine myeloma.". J Cell Bio. 67: 835–51. doi:10.1083/jcb.67.3.835. PMC 2111658. PMID 811671.
^ Rapoport T.. "Protein translocation across the eukaryotic endoplasmic reticulum and bacterial
plasma membranes.". Nature 450: 663–9. doi:10.1038/nature06384. PMID 18046402.
^ von Heijne, G.; Gavel, Y.. "Topogenic signals in integral membrane proteins". Eur J Biochem
174: 671–8. doi:10.1111/j.1432-1033.1988.tb14150.x. PMID 3134198.
^ Walter P, Ibrahimi I, Blobel G.. "Translocation of proteins across the endoplasmic reticulum.
I. Signal recognition protein binds to in-vitro-assembled polysomes synthesizing secretory protein".
JCB 91: 545–50. doi:10.1083/jcb.91.2.545. PMC 2111968. PMID 7309795.
^ Gilmore R, Blobel G, Walter P.. "Protein translocation across the endoplasmic reticulum.
I. Detection in the microsomal membrane of a receptor for the signal recognition particle".
JCB 95: 463–9. doi:10.1083/jcb.95.2.463. PMC 2112970. PMID 6292235.
^ Görlich D, Prehn S, Hartmann E, Kalies KU, Rapoport TA.. "A mammalian homolog of
SEC61p and SECYp is associated with ribosomes and nascent polypeptides during translocation".
Cell 71: 489–503. doi:10.1016/0092-8674(92)90517-G. PMID 1423609.
^ Panzner, S; Dreier, L; Hartmann, E; Kostka, S; Rapoport, TA. "Posttranslational protein
transport in yeast reconstituted with a purified complex of Sec proteins and Kar2p". Cell 81:
561–570. doi:10.1016/0092-8674(95)90077-2. ISSN 0092-8674. PMID 7758110.
^ Kober L, Zehe C, Bode J. "Optimized signal peptides for the development of high expressing
CHO cell lines". Biotechnol. Bioeng. 110: 1164–73. doi:10.1002/bit.24776. PMID 23124363.
^ von Heijne G. "Signal sequences: The limits of variation". J Mol Biol 184: 99–105. doi:10.1016/0022-2836(85)90046-4.
PMID 4032478. ^ Palazzo, Alexander F.; Springer, Michael;
Shibata, Yoko; Lee, Chung-Sheng; Dias, Anusha P.; Rapoport, Tom A.. "The Signal Sequence
Coding Region Promotes Nuclear Export of mRNA". PLoS Biology 5: e322. doi:10.1371/journal.pbio.0050322.
ISSN 1544-9173. PMC 2100149. PMID 18052610. ^ 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.. "Genome Analysis Reveals Interplay between 5′UTR
Introns and Nuclear mRNA Export
for Secretory and Mitochondrial Genes". In Snyder, Michael. PLoS Genetics 7: e1001366.
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External links Signal Peptide at the US National Library
of Medicine Medical Subject Headings SPdb
SignalP — predicts the presence and location of signal peptide cleavage sites in amino
acid sequences from different organisms.