The Ubiquitin Proteasome System
Introduction
The 2004 Nobel Prize in chemistry for the discovery of protein ubiquitination has led to an expansive area of research as novel therapeutic targets have opened up using this degradation system for use in the clinic.
The Ubiquitin Proteasome system (UPS) is an essential intracellular protein degradation system dependent on Adenosine triphosphate (ATP) for function. The system is composed of two major pieces.
- An ATP dependent reaction causes the interaction and accumulation of ubiquitin on a protein selected for degradation though interaction with three sets of enzymes, E1, E2, and E3 enzymes.
- Accumulation of Ubiquitin on the target protein marks it for degradation by the 26S proteasome. The proteasome then degrades the target proteins into peptides while the ubiquitin is recycled.
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The Ubiquitin Proteasome System is highly specific in its interaction. Manipulation of specific combinations of E2 and E3 enzymes allow for very selective targeting of a specific protein of interest without interfering with other cellular activities.
Usage of both PROteolysis TArgeting Chimeras (PROTACs) and Molecular Glues allow for studying and manipulation of the system allowing a novel pathway for treating a wide variety of diseases such as cancer, neurodegenerative disorders, and autoimmune diseases.