A chemoproteomic portrait of the oncometabolite fumarate
| Autor: | Darmood Wei, W. Marston Linehan, Laurence Florens, Chloe A. Briney, Emily C. Dykhuizen, Jordan L. Meier, Arissa E Bavari, Sarah E. Bergholtz, Abigail L. Thorpe, Norma Frizzell, Daniel W. Bak, Daniel R. Crooks, Eranthie Weerapana, Aktan Alpsoy, Michael P. Washburn, Rhushikesh A. Kulkarni, Michaella J. Levy, Jonathan H. Shrimp |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Proteomics
Skin Neoplasms Computational biology medicine.disease_cause Models Biological Article 03 medical and health sciences Fumarates Neoplastic Syndromes Hereditary Tandem Mass Spectrometry Cell Line Tumor Leiomyomatosis medicine Humans Cysteine Molecular Biology 030304 developmental biology 0303 health sciences Mutation Chemistry 030302 biochemistry & molecular biology HEK 293 cells Cancer Cell Biology Hydrogen-Ion Concentration medicine.disease 3. Good health HEK293 Cells Fumarase Proteome Uterine Neoplasms Local environment Hereditary leiomyomatosis and renal cell carcinoma Chromatography Liquid Signal Transduction |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of fumarate, a covalent oncometabolite whose accumulation marks the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). We applied a fumarate-competitive chemoproteomic probe in concert with LC-MS/MS to discover new cysteines sensitive to fumarate hydratase (FH) mutation in HLRCC cell models. Analysis of this dataset revealed an unexpected influence of local environment and pH on fumarate reactivity, and enabled the characterization of a novel a FH-regulated cysteine residue that lies at a key protein-protein interface in the SWI-SNF tumor suppressor complex. Our studies provide a powerful resource for understanding the covalent imprint of fumarate on the proteome, and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy. |
| Databáze: | OpenAIRE |
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