Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors.

High-throughput differential scanning fluorimetry of GFP-tagged proteins (HT-DSF-GTP) was applied for the identification of novel enzyme inhibitors acting by a mechanism termed: selective protein unfolding (SPU). Four different protein targets were interrogated with the same library to identify target-selective hits. Several hits selectively destabilized bacterial biotin protein ligase.

Direct and/or Indirect Roles for SUMO in Modulating Alpha-Synuclein Toxicity.

α-Synuclein inclusion bodies are a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease, and contain aggregated α-synuclein and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin and the small ubiquitin-like modifier, SUMO-1. Cell culture and animal model studies suggest that misfolded, aggregated α-synuclein is actively translocated via the cytoskeletal system to a region of the cell where other factors that help to lessen the toxic effects can also be recruited. SUMO-1 covalently conjugates to various intracellular target proteins in a way analogous to ubiquitination to alter cellular distribution, function and metabolism and also plays an important role in a growing list of cellular pathways, including exosome secretion and apoptosis.

Significance of prion and prion-like proteins in cancer development, progression and multi-drug resistance.

Prions are renowned for their role in neurodegenerative diseases in humans and animals. These are manifested as transmissible spongiform encephalopathies (TSEs) that result from the conversion of the normal glycosylphosphatidylinositol (GPI) anchored cellular prion protein (PrP(c)) to a misfolded, aggregated and pathogenic form, prion protein scrapie (PrP(Sc)) via a post-translational process followed by the accumulation of PrP(Sc) within the central nervous system. New research in this area has demonstrated that PrP is over-expressed in a variety of cancers including gastric, pancreatic and breast cancers, affecting the growth and invasiveness of these cancers as well as playing an important role in the acquisition of multi-drug resistant (MDR) gastric cancer.

A GFP-tagged nucleoprotein-based aggregation assay for anti-influenza drug discovery and antibody development.

Influenza is a viral pandemic that affects millions of people worldwide. Seasonal variations due to genetic shuffling and antigenic drifts in the influenza viruses have necessitated continual updating of therapeutics. The growing resistance to current influenza drugs has increased demand for new antivirals.

Alzheimer's Abeta fused to green fluorescent protein induces growth stress and a heat shock response.

The 42 amino acid Alzheimer's Abeta peptide is involved in the progression of Alzheimer's disease. Here we describe the effects of intracellular Abeta, produced through its attachment to either end of a green fluorescent protein, in yeast. Cells producing Abeta exhibited a lower growth yield and a heat shock response, showing that Abeta fusions promote stress in cells and supporting the notion that intracellular Abeta is a toxic molecule.