Problem
Targeting specific proteins for degradation is an area of intense research for the treatment of disease. The majority of currently available technologies, such as PROTACs, induce degradation through ubiquitination of target proteins by binding to both the target protein and ubiquitin ligases. However, this requires a ubiquitin ligase to efficiently ubiquitinate non-native substrates. The difficulty in ubiquitin ligase interacting with non-native substrates limits the number of proteins that can be effectively targeted using this approach. Ubiquitin-independent targeting strategies are needed to overcome this limitation.
Solution
The Matouschek research team has developed an alternative approach to target proteins directly to the proteasome without the need for ubiquitination. In addition to ubiquitin, the proteasome can recognize substrates through interactions with UBL-UBA proteins. UBL-UBA proteins contain an N-terminal ubiquitin-like (UBL) domain, which can bind the same receptors on the proteasome as ubiquitin chains. The Matouschek team’s technology leverages this alternative targeting mechanism to develop ubiquitin-independent targeting molecules, named “degradons”, that fuse UBL domains to a target protein binding domain, such as nanobodies and monobodies. The use of UBL domains provide several advantages over other strategies; for example, (1) UBL domains are thought to activate the proteasome, leading to enhanced degradation, and (2) targeting is not dependent on ubiquitin interacting with its native substrates.
This technology has been validated in HEK293T cells where these degradons deplete endogenous proteins, such as Shp2. Degradons are being further developed to efficiently target MIC, an intrinsically disordered protein that has proven challenging for PROTAC and small molecule inhibition design. For this and other candidates, degradons may be an advantageous design principle for synthetic proteasome targeting.
Value proposition
- Ubiquitin-independent targeting of proteins directly to the proteasome
- Sequence and structure independent targeting for degradation
- Intracellular presence of UBL domains may stimulate proteasome activity, enhancing protein degradation.
About the inventor
Dr. Andreas Matouschek is a Professor and Associate Dean for Research and Facilities at The University of Texas at Austin in the Department of Molecular Biosciences. Dr. Matouschek’s lab studies the mechanisms of protein machines, protein folding, unfolding, and degradation. His lab’s goal is to understand the biochemical mechanisms of the Ubiquitin Proteasome System (UPS) in a physiologically relevant context, in hopes to translate insights into strategies to interfere in the UPS therapeutically.
