Protein Prenylation: the Anchor of Life

MDD Group Spring 2019

What is Protein Prenylation?

Protein prenylation is a post-translational modification that consists of the attachment of 15 or 20 carbon isoprenoids to specific cysteine residues positioned near the C-termini of proteins.  In a eukaryotic cell, there are several hundred prenylated proteins including most members of the Ras superfamily and heterotrimeric G-proteins; the prenyl group serves to anchor these proteins in the membrane so that they are positioned to interact with cell surface receptors either directly or via adaptor proteins.  This means that essentially all signaling processes in eukaryotic cells require the participation of prenylated proteins for everything ranging from the regulation of cell division to stem cell differentiation and development.  Beyond biological significance, the critical role of prenylated proteins also makes them important targets for the design of new therapeutic agents for a variety of diseases


Research in the Distefano Group

Work in the Distefano Group on protein prenylation is focused in two areas: Chemical Biology and Biotechnology Applications.  In pursuit of those studies, members of the group perform a variety of different types of experiments including chemical synthesis, biochemistry, proteomics and cell culture and animal-based work.  The goal of this work is to gain insight into protein prenylation that can be used to advance biology and develop new therapeutic approaches for a broad range of diseases including cancer, Alzheimer’s disease and infectious disease.

Group News

Prenylation found to be important for key brain functions

In collaborative work between the Li and Distefano research groups published recently in Molecular Neurobiology, graduate students Wendy Qu and Kiall Suazo discovered that conditional mouse knockout of farnesyl transferase (FT) leads to reduced synaptic plasticity, memory retention, and hippocampal dendritic spine density. Prenylomic analysis using in vitro prenylation with a synthetic isoprenoid analogue allowed  specific proteins impacted to be identified.

Prenyl groups used to anchor cancer-targeting proteins on cell surface

In work spearheaded by group member Yiao Wang, chemically self-assembled nanorings designed to bind to the cancer antigens EGFR or EpCAM were anchored on activated T-cells with enzymatically installed farnesyl or geranylgeranyl groups that were then used to achieve directed cancer cell killing.  These results are reported in an article in Chemical Science.

Distefano group graduate students present at National ACS Meeting

Graduate students Shelby Auger, Kevin Park and Kiall Suazo presented their work at the National ACS Meeting in August.  Shelby presented her poster entitled "Development of a norbornene containing analogue and its applications in the study of protein prenylation", Kevin gave an oral presentation entitled "DARPin-polymer conjugates prepared by enzymatic labeling and grafting-from polymerization for tumor-targeted imaging and drug delivery" and Kiall gave an oral presentation entitled "Metabolic labeling with an alkyne probe reveals similarities and differences in the prenylomes of multiple b