Targeted protein degradation

Abstract

The ubiquitin-proteasome pathway plays a major role in cellular protein destruction and regulates fundamental cellular processes such as the cell cycle, cell signaling, and development. By altering the substrate recognition of ubiquitin-protein ligases, their robust proteolytic activity can be re-directed to recruit and accelerate the degradation of other cellular targets. Two approaches have been applied for targeted proteolysis: one entails designing a chimeric substrate receptor for recruitment of the target protein, the other involves the construction of peptide-small-molecule hybrids that bridge the interaction between the intended target and the substrate receptor of the known ubiquitin-protein ligases. The engineered ubiquitin-proteolytic apparatus operates at the post-translational level, and thus provides a new tool of reverse genetics to dissect complicated protein functions at a higher resolution than knockout or knockdown approaches functioning at the level of DNA or RNA. It also sheds light on novel therapeutic strategies for the amelioration of human disease.