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  Mass spectrometry of human leukocyte antigen class I peptidomes reveals strong effects of protein abundance and turnover on antigen presentation.

Bassani-Sternberg, M., Pletscher-Frankild, S., Jensen, L. J., & Mann, M. (2015). Mass spectrometry of human leukocyte antigen class I peptidomes reveals strong effects of protein abundance and turnover on antigen presentation. Molecular & cellular proteomics: MCP, 14(3), 658-673. doi:10.1074/mcp.M114.042812.

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Bassani-Sternberg, Michal1, Author              
Pletscher-Frankild, Sune2, Author
Jensen, Lars Juhl2, Author
Mann, Matthias1, Author              
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1Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
2external, ou_persistent22              

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 Abstract: HLA class I molecules reflect the health state of cells to cytotoxic T cells by presenting a repertoire of endogenously derived peptides. However, the extent to which the proteome shapes the peptidome is still largely unknown. Here we present a high-throughput mass-spectrometry-based workflow that allows stringent and accurate identification of thousands of such peptides and direct determination of binding motifs. Applying the workflow to seven cancer cell lines and primary cells, yielded more than 22,000 unique HLA peptides across different allelic binding specificities. By computing a score representing the HLA-I sampling density, we show a strong link between protein abundance and HLA-presentation (p < 0.0001). When analyzing overpresented proteins - those with at least fivefold higher density score than expected for their abundance - we noticed that they are degraded almost 3 h faster than similar but nonpresented proteins (top 20% abundance class; median half-life 20.8h versus 23.6h, p < 0.0001). This validates protein degradation as an important factor for HLA presentation. Ribosomal, mitochondrial respiratory chain, and nucleosomal proteins are particularly well presented. Taking a set of proteins associated with cancer, we compared the predicted immunogenicity of previously validated T-cell epitopes with other peptides from these proteins in our data set. The validated epitopes indeed tend to have higher immunogenic scores than the other detected HLA peptides. Remarkably, we identified five mutated peptides from a human colon cancer cell line, which have very recently been predicted to be HLA-I binders. Altogether, we demonstrate the usefulness of combining MS-analysis with immunogenesis prediction for identifying, ranking, and selecting peptides for therapeutic use.

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Language(s): eng - English
 Dates: 2015
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 25576301
DOI: 10.1074/mcp.M114.042812
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Title: Molecular & cellular proteomics : MCP
Source Genre: Journal
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Pages: - Volume / Issue: 14 (3) Sequence Number: - Start / End Page: 658 - 673 Identifier: -