A short binding site in the KPC1 ubiquitin ligase mediates processing of NF-κB1 p105 to p50: A potential for a tumor-suppressive PROTAC

Significance Accumulation of abnormal proteins underlies the mechanisms of numerous diseases such as malignancies and neurodegeneration. A recent development makes use of the UPS to remove such proteins. Small molecules (PROTACs) that are made of two heads—one that binds to a “universal” Ub ligase and the other that binds to the target substrate—bring the two together, which results in ubiquitination and subsequent proteasomal degradation of the target. We designed a PROTAC made of the pVHL ligase ligand and the short site of the KPC1 ligase that binds the p105 NF-ĸB precursor. The PROTAC mimics the enzymatic activity of the native KPC1 and can therefore serve as a prototype for the development of a tumor-suppressive drug.