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Chemoproteomic profiling and discovery of protein electrophiles in human cells.


ABSTRACT: Activity-based protein profiling (ABPP) serves as a chemical proteomic platform to discover and characterize functional amino acids in proteins on the basis of their enhanced reactivity towards small-molecule probes. This approach, to date, has mainly targeted nucleophilic functional groups, such as the side chains of serine and cysteine, using electrophilic probes. Here we show that 'reverse-polarity' (RP)-ABPP using clickable, nucleophilic hydrazine probes can capture and identify protein-bound electrophiles in cells. Using this approach, we demonstrate that the pyruvoyl cofactor of S-adenosyl-L-methionine decarboxylase (AMD1) is dynamically controlled by intracellular methionine concentrations. We also identify a heretofore unknown modification-an N-terminally bound glyoxylyl group-in the poorly characterized protein secernin-3. RP-ABPP thus provides a versatile method to monitor the metabolic regulation of electrophilic cofactors and discover novel types of electrophilic modifications on proteins in human cells.

SUBMITTER: Matthews ML 

PROVIDER: S-EPMC5325178 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Chemoproteomic profiling and discovery of protein electrophiles in human cells.

Matthews Megan L ML   He Lin L   Horning Benjamin D BD   Olson Erika J EJ   Correia Bruno E BE   Yates John R JR   Dawson Philip E PE   Cravatt Benjamin F BF  

Nature chemistry 20161031 3


Activity-based protein profiling (ABPP) serves as a chemical proteomic platform to discover and characterize functional amino acids in proteins on the basis of their enhanced reactivity towards small-molecule probes. This approach, to date, has mainly targeted nucleophilic functional groups, such as the side chains of serine and cysteine, using electrophilic probes. Here we show that 'reverse-polarity' (RP)-ABPP using clickable, nucleophilic hydrazine probes can capture and identify protein-boun  ...[more]

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