Targeting oncoproteins with a positive selection assay for protein degraders.

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase.

Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion.

Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion.

Peptidic degron for IMiD-induced degradation of heterologous proteins.

Current systems for modulating the abundance of proteins of interest in living cells are powerful tools for studying protein function but differ in terms of their complexity and ease of use. Moreover, no one system is ideal for all applications, and the best system for a given protein of interest must often be determined empirically. The thalidomide-like molecules (collectively called the IMiDs) bind to the ubiquitously expressed cereblon ubiquitin ligase complex and alter its substrate specificity such that it targets the IKZF1 and IKZF3 lymphocyte transcription factors for destruction.

Requirement for natively unstructured regions of mesoderm development candidate 2 in promoting low-density lipoprotein receptor-related protein 6 maturation.

Proteins of the low-density lipoprotein receptor family (LRPs) are complex, multimodular type I transmembrane receptors. Productive maturation of these proteins relies on an ER-resident protein called mesoderm development candidate 2 (MESD) in mammals and Boca in Drosophila. We show here that MESD contains a central folded domain flanked by natively unstructured regions required to facilitate maturation of LRP6.