University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, Membrane Enzymology, Groningen, the Netherlands.
University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, Structural Biology, Groningen, the Netherlands.
Nat Struct Mol Biol. 2018 Jun;25(6):515-521. doi: 10.1038/s41594-018-0076-y. Epub 2018 Jun 5.
Human ASCT2 belongs to the SLC1 family of secondary transporters and is specific for the transport of small neutral amino acids. ASCT2 is upregulated in cancer cells and serves as the receptor for many retroviruses; hence, it has importance as a potential drug target. Here we used single-particle cryo-EM to determine a structure of the functional and unmodified human ASCT2 at 3.85-Å resolution. ASCT2 forms a homotrimeric complex in which each subunit contains a transport and a scaffold domain. Prominent extracellular extensions on the scaffold domain form the predicted docking site for retroviruses. Relative to structures of other SLC1 members, ASCT2 is in the most extreme inward-oriented state, with the transport domain largely detached from the central scaffold domain on the cytoplasmic side. This domain detachment may be required for substrate binding and release on the intracellular side of the membrane.
人源 ASCT2 属于 SLC1 家族的继发性转运蛋白，特异性地转运小分子中性氨基酸。ASCT2 在癌细胞中上调，并且作为许多逆转录病毒的受体，因此它作为一个潜在的药物靶点具有重要意义。在这里，我们使用单颗粒 cryo-EM 技术在 3.85-Å 分辨率下确定了功能未修饰的人源 ASCT2 的结构。ASCT2 形成三聚体复合物，每个亚基包含一个转运和支架结构域。支架结构域上突出的细胞外延伸部分形成了预测的逆转录病毒对接位点。与其他 SLC1 成员的结构相比，ASCT2 处于最极端的内向状态，转运结构域在细胞质侧与中央支架结构域大部分分离。这种结构域分离可能是在膜的细胞内侧结合和释放底物所必需的。
