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Scientific background

For a brief description of the SignalP method please consult the article abstracts.

Biological background

Interest in signal peptides has for a long time been one of the hot topics in bioinformatics. The importance of signal peptides was emphasized in 1999 when G√ľnter Blobel received the Nobel Prize in physiology or medicine for his discovery "proteins have intrinsic signal that govern their transport and localization in the cell". He pointed out the importance of defined peptide motifs for targeting proteins to their site of function. The press release can be read here

Signal peptides

Many different types of secretory signals are found. For the SignalP server we have focused on prediction of classical signal peptides, which are the far most common type of signal peptide cleaved by signal peptidase I (SPase). In eukaryotes the signal peptide target the protein to the endoplasmatic reticulum for later passage to the secretory pathway. In the ER the protein might undergo different post translational modifications, such as glycolation. In bacteria the protein is targeted directly to the cell membrane.

Signal anchors

Signal anchors are "uncleaved signal peptides" which has no SPase recognition site, thus is not cleaved. Introduction of the HMM model in SignalP version 2, made it possible to distinguish signal peptides from signal anchors. Signal anchors are type II membrane proteins and can be found in SWISS-PROT by searching for the flowing in the feature table (FT) field, "SIGNAL-ANCHOR (TYPE-II MEMBRANE PROTEIN)".

Signal peptides versus signal anchors

Other signals for secretion

Many different signal motifs are found and used for different targeting to various subcellular localizations. SignalP was not developed to predict these diverse targeting signals, but is mentioned here as background knowledge.

TAT (Twin-arginine translocation)

Twin arginine signal peptides contain a conserved twin argine motif (RR) within the signal peptide. These signal peptides are in general longer and less hydrophobic than the classical signal peptides predicted by
SignalP. Often, SignalP, is capable of correctly classifying these proteins as secretory, although the position of the predicted cleavage site is wrong. More information about Tat signal peptides can be found at Interpro using the following accession number IPR006311.

For prediction of prokaryotic twin arginine signal peptides we recommend using the TatP server.

Lipo proteins

Prokaryotic lipoprotein cleavage sites are not predicted using SignalP. Prokaryotic lipoproteins are cleaved by a specific lipoprotein signal peptidase, Lsp or signal peptidase II. This peptidase recognizes a conserved sequence and cuts upstream of a cysteine residue to which a glyceride-fatty acid lipid is attached. The cleavage sites of these proteins differ considerably from those cleaved by the standard prokaryotic signal peptidase (SpaseII).

More information about prokaryotic lipoproteins and their consensus sequence can be found in the PROSITE entry PROKAR_LIPOPROTEIN. Information can also be found at Interpro IPR000437.

For prediction of prokaryotic lipoproteins we recommend using the LipoP server.

Non-classical and leaderless secreted proteins

Not all secretory proteins carry signal peptides or similar targeting signals. Some proteins enter the non-classical secretory pathway without any currently known sequence motif. These proteins are mostly growth factors and extracellular matrix binding proteins. For prediction of such proteins we recommend the SecretomeP server.


Henrik Nielsen,