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A chemoproteomic portrait of the oncometabolite fumarate

Kulkarni, Rhushikesh A ; Bak, Daniel W ; Wei, Darmood ; Bergholtz, Sarah E ; Briney, Chloe A ; Shrimp, Jonathan H ; Alpsoy, Aktan ; Thorpe, Abigail L ; Bavari, Arissa E ; Crooks, Daniel R ; Levy, Michaella ; Florens, Laurence ; Washburn, Michael P ; Frizzell, Norma ; Dykhuizen, Emily C ; Weerapana, Eranthie ; Linehan, W Marston ; Meier, Jordan L

Nature chemical biology, 2019-04, Vol.15 (4), p.391-400 [Periódico revisado por pares]

United States: Nature Publishing Group

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A chemoproteomic portrait of the oncometabolite fumarate
Autor: Kulkarni, Rhushikesh A ; Bak, Daniel W ; Wei, Darmood ; Bergholtz, Sarah E ; Briney, Chloe A ; Shrimp, Jonathan H ; Alpsoy, Aktan ; Thorpe, Abigail L ; Bavari, Arissa E ; Crooks, Daniel R ; Levy, Michaella ; Florens, Laurence ; Washburn, Michael P ; Frizzell, Norma ; Dykhuizen, Emily C ; Weerapana, Eranthie ; Linehan, W Marston ; Meier, Jordan L
Assuntos: Cancer ; Cell culture ; Cell Line, Tumor ; Chromatography, Liquid - methods ; Cysteine ; Fumarate hydratase ; Fumarates - metabolism ; HEK293 Cells ; Humans ; Hydrogen-Ion Concentration ; Leiomyomatosis - genetics ; Leiomyomatosis - metabolism ; Models, Biological ; Mutation ; Neoplastic Syndromes, Hereditary - genetics ; Neoplastic Syndromes, Hereditary - metabolism ; Proteins ; Proteomes ; Proteomics ; Renal cell carcinoma ; Signal Transduction ; Skin Neoplasms - genetics ; Skin Neoplasms - metabolism ; Tandem Mass Spectrometry - methods ; Tumors ; Uterine Neoplasms - genetics ; Uterine Neoplasms - metabolism
É parte de: Nature chemical biology, 2019-04, Vol.15 (4), p.391-400
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R.A.K. and D.W.B. contributed equally to this work.
R.A.K., D.W.B., E.W. and J.L.M. designed experiments. R.A.K. and D.W.B. performed all chemical proteomic labeling and enrichment experiments. D.W.B. and E.W. performed all LC-MS/MS studies and relative stoichiometry analyses of IA-alkyne enrichment experiments. R.A.K. and A.E.B. synthesized compounds. R.A.K., S.E.B. and J.H.S. performed all cell-based analyses and co-immunoprecipitation experiments. C.A.B. assisted with cell-based analyses and performed S-succination reversibility studies. J.L.M., D.W.B., A.L.T. and R.A.K. performed bioinformatics analyses. D.W. and W.M.L. performed HLRCC spheroid growth inhibition studies and assisted with SWI/SNF analyses. A.A. and E.C.D. performed glycerol gradient fractionation analysis of SWI/SNF complex and SNF5-dependent gene expression in HLRCC cell lines. N.F. provided the S-succination antibody and literature analysis. W.M.L. and D.R.C. provided HLRCC cell lines and advised experimental design. M.P.W., L.F. and M.L. performed whole proteome MudPIT S-succination analyses of HLRCC cells. R.A.K. and J.L.M. analyzed data and wrote the manuscript with input from all authors.
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Descrição: Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Toward 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 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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A chemoproteomic portrait of the oncometabolite fumarate

United States: Nature Publishing Group

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