Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis.

ABSTRACT: With more than 450 members, the solute carrier (SLC) group of proteins represents the largest class of transporters encoded in the human genome. Their several-pass transmembrane domain structure and hydrophobicity contribute to the orphan status of many SLCs, devoid of known cargos or chemical inhibitors. We report that SLC proteins belonging to different families and subcellular compartments are amenable to induced degradation by heterobifunctional ligands. Engineering endogenous alleles via the degradation tag (dTAG) technology enabled chemical control of abundance of the transporter protein, SLC38A2. Moreover, we report the design of d9A-2, a chimeric compound engaging several members of the SLC9 family and leading to their degradation. d9A-2 impairs cellular pH homeostasis and promotes

SUBMITTER: Bensimon A 

PROVIDER: S-EPMC7303955 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature