Hyun Suk Lim

Hyun Suk Lim

Associate Professor
Pohang University of Science and Technology
 (82) 54-279-2131


Targeted Protein Degradation via the N-end Rule Pathway

A proteolysis targeting chimera, PROTAC, is a heterobifunctional molecule having two small-molecules connected by a linker. One small-molecule binds to a target protein, for example, a disease target protein, while the other small-molecule engages an E3 ubiquitin ligase. Thus, this chimeric molecule is able to recruit the target protein to the E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target protein by the 26S proteasome. Due to the unique mode of action capable of effectively depleting disease-associated proteins, PROTAC technology is emerged as a novel, promising therapeutic strategy. Here, we present a new class of PROTAC molecules that degrade a target protein via the N-end rule pathway.

The N-end rule is a conserved proteolytic system that degrade cellular proteins having N-terminal degradation signals, N-degrons, which are recognized by the ubr box proteins, E3 ligases. So, the N-terminal amino acid residue of a protein determines its half-life, and the N-end rule pathway governs the rate of protein degradation. We designed chimeric molecules in which a staple peptide targeting NCOA-1 and a ligand for ubr box proteins covalently linked by various linkers. This bifunctional molecule was found to effectively degrade the target protein, NCOA-1, a transcriptional co-activator, in cells, thereby inhibiting cancer cell migration and metastasis. This new PROTACS strategy could be particularly useful when targeting cells that do not express the E3 ligases targeted by current PROTACs, for example, celebron.


Hyun-Suk Lim and Yeongju Lee


Pohang University of Science and Technology, POSTECH, Pohang 37673, South Korea

Lecture Images

Hyun Suk Lim presenting at APS2019 Hyun Suk Lim presenting at APS2019 Hyun Suk Lim presenting at APS2019