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PXD009378

PXD009378 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleA chemoproteomic portrait of the oncometabolite fumarate
DescriptionHereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth and survival. Understanding these mechanisms and developing biomarkers to identify their presence thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of the covalent targets of fumarate, an oncometabolite whose accumulation marks the genetic cancer predisposition syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). First, we validate the ability of known and novel chemoproteomic probes to report on concentration-dependent fumarate reactivity in vitro. Next, we apply these probes in concert with LC-MS/MS to identify cysteine residues sensitive to either fumarate treatment or fumarate hydratase (FH) mutation in untransformed and HLRCC cell models, respectively. Mining this data to understand the structural determinants of fumarate reactivity led to the discovery of an unexpected anti-correlation with nucleophilicity, indicating a novel influence of pH on fumarate-cysteine interactions. Finally, we show that many fumarate-sensitive and FH-regulated cysteines are found in functional protein domains, and perform functional studies of a fumarate-sensitive cysteine in SMARCC1 that lies at a key protein-protein interface in the SWI-SNF tumor suppressor complex. Our studies provide a powerful resource for understanding the influence of fumarate on reactive cysteine residues, and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.
HostingRepositoryPRIDE
AnnounceDate2018-11-27
AnnouncementXMLSubmission_2019-06-17_03:28:59.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterDaniel Bak
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListiodoacetamide derivatized residue
InstrumentLTQ Orbitrap
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-04-03 08:14:14ID requested
12018-11-27 03:13:51announced
22019-06-17 03:29:01announcedUpdated publication reference for PubMed record(s): 30718813.
Publication List
Kulkarni RA, Bak DW, Wei D, Bergholtz SE, Briney CA, Shrimp JH, Alpsoy A, Thorpe AL, Bavari AE, Crooks DR, Levy M, Florens L, Washburn MP, Frizzell N, Dykhuizen EC, Weerapana E, Linehan WM, Meier JL, A chemoproteomic portrait of the oncometabolite fumarate. Nat Chem Biol, 15(4):391-400(2019) [pubmed]
Keyword List
curator keyword: Biomedical
submitter keyword: UOK262, hereditary leiomyomatosis and renal cell carcinoma (HLRCC), Fumarate hydratase (FH), Fumarate, Succination, Cysteine reactivity, LC-MSMS
Contact List
Eranthie Weerapana
contact affiliationChemistry Department, Boston College, USA
contact emaileranthie@bc.edu
lab head
Daniel Bak
contact affiliationBoston College
contact emailbakd@bc.edu
dataset submitter
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Dataset FTP location
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