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

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

Cell chemical biology (2020-05-11)
Ariel Bensimon, Mattia D Pizzagalli, Felix Kartnig, Vojtech Dvorak, Patrick Essletzbichler, Georg E Winter, Giulio Superti-Furga
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 cell death in a range of cancer cell lines. These findings open the era of SLC-targeting chimeric degraders and demonstrate potential access of multi-pass transmembrane proteins of different subcellular localizations to the chemically exploitable degradation machinery.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pomalidomide, ≥98% (HPLC)
Sigma-Aldrich
Saponin, for molecular biology, used as non-ionic surfactant
Sigma-Aldrich
5-(N-Ethyl-N-isopropyl)amiloride
Sigma-Aldrich
Poly-L-lysine hydrobromide, mol wt 70,000-150,000, lyophilized powder, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
Anti-HA−Peroxidase antibody, Mouse monoclonal, clone HA-7, purified from hybridoma cell culture
Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)