Dataset Information

Integrated modeling of the major events in the MHC class I antigen processing pathway.

ABSTRACT: Rational design of epitope-driven vaccines is a key goal of immunoinformatics. Typically, candidate selection relies on the prediction of MHC-peptide binding only, as this is known to be the most selective step in the MHC class I antigen processing pathway. However, proteasomal cleavage and transport by the transporter associated with antigen processing (TAP) are essential steps in antigen processing as well. While prediction methods exist for the individual steps, no method has yet offered an integrated prediction of all three major processing events. Here we present WAPP, a method combining prediction of proteasomal cleavage, TAP transport, and MHC binding into a single prediction system. The proteasomal cleavage site prediction employs a new matrix-based method that is based on experimentally verified proteasomal cleavage sites. Support vector regression is used for predicting peptides transported by TAP. MHC binding is the last step in the antigen processing pathway and was predicted using a support vector machine method, SVMHC. The individual methods are combined in a filtering approach mimicking the natural processing pathway. WAPP thus predicts peptides that are cleaved by the proteasome at the C terminus, transported by TAP, and show significant affinity to MHC class I molecules. This results in a decrease in false positive rates compared to MHC binding prediction alone. Compared to prediction of MHC binding only, we report an increased overall accuracy and a lower rate of false positive predictions for the HLA-A*0201, HLA-B*2705, HLA-A*01, and HLA-A*03 alleles using WAPP. The method is available online through our prediction server at http://www-bs.informatik.uni-tuebingen.de/WAPP

SUBMITTER: Donnes P

PROVIDER: S-EPMC2279325 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Integrated modeling of the major events in the MHC class I antigen processing pathway.

Dönnes Pierre P Kohlbacher Oliver O

Protein science : a publication of the Protein Society 20050629 8

Rational design of epitope-driven vaccines is a key goal of immunoinformatics. Typically, candidate selection relies on the prediction of MHC-peptide binding only, as this is known to be the most selective step in the MHC class I antigen processing pathway. However, proteasomal cleavage and transport by the transporter associated with antigen processing (TAP) are essential steps in antigen processing as well. While prediction methods exist for the individual steps, no method has yet offered an i ...[more]

PMID: 15987883

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Project description:The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for "T-cell epitopes associated with impaired peptide processing." TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer's related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing.

Dataset Information

Integrated modeling of the major events in the MHC class I antigen processing pathway.

Publications

Integrated modeling of the major events in the MHC class I antigen processing pathway.

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