CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
Cell Chem Biol. 2020 Jun 18;27(6):728-739.e9. doi: 10.1016/j.chembiol.2020.04.003. Epub 2020 May 7.
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.
拥有超过 450 个成员的溶质载体（SLC）蛋白家族是人类基因组中编码的最大的转运蛋白家族。其多次跨膜结构域和疏水性导致许多 SLC 成为孤儿，缺乏已知的货物或化学抑制剂。我们报告说，属于不同家族和亚细胞区室的 SLC 蛋白可通过双功能配体诱导降解。通过降解标签（dTAG）技术对内源性等位基因进行工程改造，可实现对转运蛋白 SLC38A2 的丰度进行化学控制。此外，我们还报告了 d9A-2 的设计，这是一种嵌合化合物，可与 SLC9 家族的多个成员结合，并导致它们的降解。d9A-2 破坏细胞内 pH 稳态，并在多种癌细胞系中促进细胞死亡。这些发现开创了 SLC 靶向嵌合降解剂的时代，并证明了不同亚细胞定位的多跨膜蛋白可进入可化学利用的降解机制。
