期刊
MOLECULAR & CELLULAR PROTEOMICS
卷 8, 期 12, 页码 2700-2714出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/mcp.M900310-MCP200
关键词
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资金
- Bijzonder Onderzoeksfonds (BOF) [B/00757/01, B/05959/01, 01D29405]
- Fonds voor Wetenschappelijk Onderzoek-Vlaanderen
- European Union [LSHB-CT-2005-019067]
- Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen)
- Ghent University [GOA 01G01507]
Caspase-3 and -7 are considered functionally redundant proteases with similar proteolytic specificities. We performed a proteome-wide screen on a mouse macrophage lysate using the N-terminal combined fractional diagonal chromatography technology and identified 46 shared, three caspase-3-specific, and six caspase-7-specific cleavage sites. Further analysis of these cleavage sites and substitution mutation experiments revealed that for certain cleavage sites a lysine at the P5 position contributes to the discrimination between caspase-7 and -3 specificity. One of the caspase-7-specific substrates, the 40 S ribosomal protein S18, was studied in detail. The RPS18-derived P6-P5' undecapeptide retained complete specificity for caspase-7. The corresponding P6-P1 hexapeptide still displayed caspase-7 preference but lost strict specificity, suggesting that P' residues are additionally required for caspase-7-specific cleavage. Analysis of truncated peptide mutants revealed that in the case of RPS18 the P4-P1 residues constitute the core cleavage site but that P6, P5, P2', and P3' residues critically contribute to caspase-7 specificity. Interestingly, specific cleavage by caspase-7 relies on excluding recognition by caspase-3 and not on increasing binding for caspase-7. Molecular & Cellular Proteomics 8:2700-2714, 2009.
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