A compact, portable degron tool derived from the 3′UTR of MTCH2 for tunable degradation of proteins

ABSTRACT Targeted protein degradation relies on short sequence elements, termed degrons, that direct proteins to the cellular degradation machinery. Here, we report a nine-amino-acid degron (FYTVWRAFL) derived from the 3′ untranslated region (UTR) of human MTCH2 and demonstrate its utility as a tuneable protein-degradation tool. When appended to the C-terminus of proteins, FYTVWRAFL induces rapid and robust degradation by the ubiquitin-proteasome system. Using pharmacological inhibition and genetic perturbation, we show that degradation mediated by this degron is dependent on the E3 ubiquitin ligase MDM2. Structural modeling revealed that FYTVWRAFL interacts with the hydrophobic cleft of MDM2 in a manner similar to the p53 degron. Three hydrophobic residues form the core interaction interface. By systematic mutagenesis of these residues, we generated a panel of degron variants that confer graded levels of protein stability. We demonstrate the versatility of this system by achieving tunable expression of the endogenous protein Elm1 in Saccharomyces cerevisiae . Collectively, our study establishes a compact, transportable, and tunable degron system as a robust toolkit for quantitative control of protein abundance across eukaryotic systems.