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Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease choroideremia.

Original publication

DOI

10.1038/s41557-019-0237-6

Type

Journal article

Journal

Nat Chem

Publication Date

2019

Volume

11

Pages

552 - 561

Keywords

Adaptor Proteins, Signal Transducing/genetics Alkynes/*chemistry Animals Cell Line Gene Knockout Techniques Humans Mass Spectrometry Mice, Knockout Molecular Probes/*chemistry *Protein Prenylation/drug effects Proteins/*analysis/chemistry Proteome/*analysis/chemistry Proteomics/*methods