Project Details
Description
PROJECT SUMMARY
Protein prenylation is characterized by the addition of farnesyl (C15) or geranylgeranyl (C20) isoprenoids to
cysteine residues located near the C-termini of different proteins. Although originally considered to be a rare
modification, it is now clear that protein prenylation is widespread in eucaryotes and is of critical importance for
a variety of proteins involved in oncogenesis, secretion, nuclear structure, and signal transduction. It has been
estimated that as many as 2% of all proteins in mammalian cells are isoprenylated. This prevalence, coupled
with the central role that many of these modified proteins play in cellular signaling, underscores the
significance of this post-translational modification. Prenylation inhibitors were initially developed as therapeutic
agents for cancer treatment. With the development of precision medicine approaches that target specific Ras-
driven cancers, several clinical trials are ongoing. These inhibitors are also being investigated for the treatment
of a wide variety of other disease including malaria, viral infections, Parkinson's disease and progeria.
Two closely linked critical questions in the field of prenylation research concern what proteins are prenylated
and how do they change in disease? What are clearly necessary are global methods that can compare the
prenylomes in normal and disease states and allow those prenylated proteins whose levels change to be
identified. If this were possible, it would reveal new targets for therapeutic intervention in these debilitating
diseases. To address this, new isoprenoid probes for improved metabolic labeling will be synthesized and
methods to decrease sample complexity and improve probe delivery will be developed. These will be utilized in
quantitative proteomic experiments in cell culture and mouse models for disease. Another critical set of
questions is what controls prenylation efficiency and is how is prenylation regulated? To address these
questions, what are needed are strategies that allow the process of protein prenylation to be assayed in real
time in live cells. This would allow prenylation reactions to be studied in a holistic manner in the presence of all
relevant cellular components. It could open also up additional avenues for therapeutic intervention since it
could reveal new regulatory interactions that could be targeted. To accomplish this, cell penetrating peptides
with caged cysteine residues that mask their site of prenylation will be prepared and their subsequent
prenylation monitored via microscopy after uncaging in a temporally controlled manner. Complementary
experiments with full-length proteins, prepared by sortase ligation, containing the same light activated trigger
will be used to explore potential interactions with chaperone proteins that may not be observed with the simpler
peptide-based models.
Status | Active |
---|---|
Effective start/end date | 4/5/21 → 1/31/25 |
Funding
- National Institute of General Medical Sciences: $317,052.00
- National Institute of General Medical Sciences: $453,068.00
- National Institute of General Medical Sciences: $317,907.00
- National Institute of General Medical Sciences: $352,762.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.