An algorithm for the prediction of proteasomal cleavages

Kuttler, Christina; Nussbaum, Alexander K.; Dick, Tobias P.; Rammensee, Hans Georg; Schild, Hansjörg; Hadeler, K. P.

doi:10.1006/jmbi.2000.3683

Cited by 141 publications

(72 citation statements)

References 42 publications

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“…The sequences of gp96-associated peptides not only provide information on their immunological potencies but also on the specificity of the antigen-processing machinery and, in particular, on the specificity of the endopeptidase systems that generate antigenic peptides from their source proteins. The three available algorithms for proteasomal cleavage are based on experimental cleavage of synthetic peptides or of elastase as a model protein and on the C termini of known MHC class I molecule-bound peptides (33)(34)(35)(36)(37). However, none of these algorithms could predict the C termini of all the gp96-associated peptides correctly.…”

Section: Gp96-associated Peptidesmentioning

confidence: 99%

“…The primary products of the cleavage by these systems inside cells have not been identified and analyzed yet, likely because of their low abundance and rapid degradation. The information on the specificity of the proteasomes available to date is derived from in vitro analyses of the cleavage of synthetic peptides or of the model protein elastase by proteasomes isolated from cells (33)(34)(35)(36)(37). Likewise, the information on the specificity of the TPPII system is deduced from in vitro experiments with purified enzyme complexes and a model polypeptide.…”

Section: Gp96-associated Peptidesmentioning

confidence: 99%

“…We therefore compared the sequences of the peptides that we had isolated from gp96 to the cleavage sites predicted by the three available prediction algorithms for proteasomal cleavage. These algorithms are based on experiments with proteasome that were purified from cells and, as substrates, synthetic peptides (Fragpredict) (33,34) or human elastase as model protein (Paproc) (35,36) or on the C termini of MHC class I ligands (NetChop) (37) (Table IV). The C-terminal amino acids of the nine internal protein fragments associated with gp96 were phenylalanine (three times), asparagines (two times), and glutamic acid, arginine, proline, and leucine (one time each).…”

Section: Gp96-associated Peptidesmentioning

confidence: 99%

“…(35,36), and NetChop (37) were used to predict the proteasome cleavage sites. Dashes indicate that the cleavage was predicted correctly, negative numbers indicate N-terminal deviations of the predicted from the correct cleavage site, and positive numbers indicate C-terminal deviations.…”

Section: Gp96-associated Peptidesmentioning

confidence: 99%

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Testing the Role of gp96 as Peptide Chaperone in Antigen Processing

Demine

Walden

2005

Journal of Biological Chemistry

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gp96 is a 96-kDa glycoprotein of the endoplasmic reticulum that is believed to be involved in antigen processing as an intermediate carrier of peptides for presentation by major histocompatibility complex (MHC) class I molecules. This function implies that gp96 carries a large array of different peptides that represent the antigenicity of the cell and can serve all MHC class I molecules. So far, the evidence regarding these peptides is largely indirect and based on experiments where mice immunized with gp96 from tumor or virus-infected cells developed T cellular immune responses with the corresponding specificities. We analyzed by mass spectrometry peptides isolated from gp96 and found a number of different peptides derived from the proteins of different cellular compartments but mostly cytoplasm and nucleus. The sequences of these peptides provide information on the specificity of antigen processing and reveal structural requirements for binding to gp96 that only partially correspond to those of peptides presented by MHC class I molecules. The yield of peptides extracted from gp96 was far substoichiometric with an estimated occupancy of this chaperone of between 0.1% and 0.4%. These results strongly argue against a regular role for gp96 as a peptide chaperone in antigen processing.

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Section: Gp96-associated Peptidesmentioning

confidence: 99%

Section: Gp96-associated Peptidesmentioning

confidence: 99%

Section: Gp96-associated Peptidesmentioning

confidence: 99%

Section: Gp96-associated Peptidesmentioning

confidence: 99%

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Testing the Role of gp96 as Peptide Chaperone in Antigen Processing

Demine

Walden

2005

Journal of Biological Chemistry

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“…Collected data of proteasome cleavage products (e.g. (9,10)) were incorporated into predictive algorithms (11)(12)(13). In particular, it has been shown based on an analysis of about 300 naturally processed peptides, that both the C-terminal residue and its flanking residue play a role in determination of proteasome cleavage specificity (10).…”

Section: Introductionmentioning

confidence: 99%

A melanoma multiepitope polypeptide induces specific CD8+ T-cell response

Levy

Pitcovski

Frankenburg

et al. 2007

Cellular Immunology

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Strategies using epitope-based vaccination are being considered for melanoma immunotherapy, in an attempt to overcome failure of other modalities. In the present study, we designed and produced a multiepitope polypeptide for melanoma (MEP-mel), which contains three repeats of four antigenic epitopes (gp100:209-217 (210M); gp100:280-288 (288V); Mart1:26-35 (27L); tyrosinase: 368-376 (370D). The peptides were attached to each other by linkers containing sequences recognized by the proteasome, to improve protein cleavage and antigen presentation. The results show that peptidespecific T cells produced IFN-γ when stimulated with MEP-mel-transfected dendritic cells. The presentation of peptides by MEP-mel-transfected dendritic cells was proteasome-dependent and was more long-lasting than the presentation of exogenously delivered native peptides. When dendritic cells were loaded with MEP-mel protein, weak cross presentation was induced. The production of multiepitope molecules based on several peptides linked by sequences sensitive to proteasomal cleavage represents a promising new tool for the improvement of cancer immunotherapy.

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MHC Class I Antigen Processing System

Yewdell

2010

Topley &Amp; Wilson's Microbiology and Microbial Infections

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An algorithm for the prediction of proteasomal cleavages

Cited by 141 publications

References 42 publications

Testing the Role of gp96 as Peptide Chaperone in Antigen Processing

Testing the Role of gp96 as Peptide Chaperone in Antigen Processing

A melanoma multiepitope polypeptide induces specific CD8+ T-cell response

MHC Class I Antigen Processing System

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