Profiling of lipid-modified proteins have been made efficient through the use of mass spectrometry-based chemical proteomics. In particular for prenylated proteins, an analogue of the native isoprenoids farnesyl and geranylgeranyl that bears a handle for succeeding enrichment steps is used to metabolically tag the prenylome. Statins, inhibitors of the mevalonate pathway, are often used to diminish the production of the native isoprenoids and thereby improve probe incorporation. In the presence of lovastatin, we have identified 77 prenylated proteins bearing prenylation motifs in COS-7 using a single analogue that labels both farnesylated and geranylgeranylated proteins. Novel prenylation substrates were identified, of which some were previously shown to be substrates for prenylation at the peptide level. In the absence of perturbation induced by statins, a total of 60 proteins were identified at their endogenous levels. We extended our profiling analysis into other cultured cells and brain cell lines (astrocytes, neurons, and microglia), affording a varied list of prenylated proteins identified. Whether the differences come from their ability to take up the probe or the inherent efficiency of their prenylation activity, our results showed that metabolic labeling of prenylated proteins is deemed cell line-dependent. Therefore, careful evaluation of the cell line models through initial metabolic labeling is a prerequisite in determining the levels of prenylated proteins detectable by chemical proteomic approaches. This sets the limitation when pursuing potential targets such as in Alzheimer’s disease and other brain pathologies. Furthermore, we showed how chemical proteomics can be used as a tool to evaluate the global effect on the prenylated proteins when the transport of small GTPases (a subset of prenylated proteins) by SmgGDS proteins is perturbed in lung cancer cells. <br/>

Insights into the chemical proteomic profiling of prenylated proteins in a diverse range of cell lines

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.