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Non Classical Secretion

For targeting a protein to the extracellular space, it has for a long time been believed that an N-terminal signal peptide was strictly required. Recent studies, however, have shown that several extracellular proteins, such as FGF-1, FGF-2, IL-1 and galectins found in the extracellular matrix, can be exported without a classical N-terminal signal peptide. Furthermore, nuclear HMGB1 and viral proteins, such as HIV-tat or herpes simplex virus VP22, have been shown to enter the non-classical secretory pathway. Secretion of proteins without an N-terminal signal peptide is currently known as leaderless secretion or the non-conventional/non-classical secretory pathway.

This is a catalogue of verified and predicted human proteins undergoing non-classical secretion, i.e. proteins without an N-terminal signal peptide.

Verified non-classical secreted proteins in Humans
Predicted non-classical secreted proteins in Humans


Human proteins from Swiss-Prot entering the non-classical sectory pathway.



The list of predicted human proteins, entering the non-classical secretory pathway, is generated using a sequence based prediction method SecretomeP. The method is based on protein features like different physiochemical properties, post-translational modifications or structural motifs.

Version 3.05 (April 2005) of the human IPI database have been analyzed by SecretomeP. Links to the results are listed below. Proteins are ranked after highest neural network score.
  • List A: Contain all proteins from IPI ranked by SecretomeP.

  • List B: Proteins predicted to have a sigal peptide from list A are removed.

  • List C: Contain only proteins from list B where the odds is > 5.0.

  • List D: Is a fasta file of all proteins from list C which have a methionine start codon. This list is sorted by IPI accession number and begin with the lowest.

  • List E: Are proteins from List D which are not predicted to be transmembrane proteins after running TMHMM. List E is in fasta file format and sorted by IPI accession number and begin with the lowest.

The list below is the top-thirty highest scoring human entries from SecretomeP and after stratifications mentioned above (No signal peptide, odds >5, M start codon, TMHMM = 0). All entries share significant homology to mouse sequences.

    IPI                       NN          Description in NR
    00051307.4     0.985     Similar to hypothetical protein zc477.8
    00006018.1     0.974     Hypothetical protein DKFZp434N0450
    00008308.1     0.972     HGC6.3 protein
    00397223.2     0.971     Similar to SMART/HDAC1 associated repressor protein
    00444615.1     0.970     Hypothetical protein FLJ45073
    00442531.1     0.968     Hypothetical protein FLJ27057
    00234905.7     0.968     Unnamed protein product
    00097028.1     0.968     Hypothetical protein XP_087208
    00456168.1     0.964     Hypothetical protein XP_498608
    00046805.1     0.964     Hypothetical protein XP_059473
    00444711.1     0.963     Hypothetical protein FLJ44998
    00176065.1     0.962     Hypothetical protein XP_211768
    00553011.1     0.961     Mitogen-activated protein kinase associated protein 1 (fragment)
    00455120.1     0.961     Hypothetical protein XP_499572
    00402230.1     0.961     Similar to Mucin 4 (Tracheobronchial mucin)
    00386457.1     0.961     OK/SW-CL.41
    00014395.1     0.961      -
    00450969.1     0.959     Hypothetical protein
    00444414.1     0.959     Hypothetical protein FLJ45598
    00384290.3     0.959     Hypothetical protein
    00454901.1     0.958     Similar to CG7709-PA
    00402418.1     0.958     Hypothetical protein XP_379189
    00235542.1     0.958     Hypothetical protein XP_295126
    00457129.1     0.957     Similar to KIAA0754 protein.
    00031070.1     0.957     Hypothetical protein
    00445342.1     0.956     Hypothetical protein FLJ44184
    00552576.1     0.955     Novel protein
    00022319.1     0.955     NPD002
    00445898.1     0.953     Hypothetical protein FLJ43291
    00434875.2     0.953     Hypothetical protein LOC130074

The SecretomeP method complements the highly popular method for detection of classically secreted proteins, SignalP.
More details about the SecretomeP method can be found in the paper:

"Feature based prediction of non-classical and leaderless protein secretion"
J. Dyrløv Bendtsen, L. Juhl Jensen, N. Blom, G. von Heijne and S. Brunak.
Protein Eng Des Sel, 2004 17(4), 349-356.

Predictions can be made at SecretomeP server.

This page is part of the BioSapiens Network funded by the European Commission within its FP6 programme, under the thematic area "Life science, genomics and biotechnology for health", contract number LHSG-CT-2003-503265.


Zenia Marian Larsen,