Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Struct Mol Biol. 2018 Jun;25(6):522-527. doi: 10.1038/s41594-018-0072-2. Epub 2018 Jun 5.
Recent advances in understanding intracellular amino acid transport and mechanistic target of rapamycin complex 1 (mTORC1) signaling shed light on solute carrier 38, family A member 9 (SLC38A9), a lysosomal transporter responsible for the binding and translocation of several essential amino acids. Here we present the first crystal structure of SLC38A9 from Danio rerio in complex with arginine. As captured in the cytosol-open state, the bound arginine was locked in a transitional state stabilized by transmembrane helix 1 (TM1) of drSLC38A9, which was anchored at the groove between TM5 and TM7. These anchoring interactions were mediated by the highly conserved WNTMM motif in TM1, and mutations in this motif abolished arginine transport by drSLC38A9. The underlying mechanism of substrate binding is critical for sensitizing the mTORC1 signaling pathway to amino acids and for maintenance of lysosomal amino acid homeostasis. This study offers a first glimpse into a prototypical model for SLC38 transporters.
最近在理解细胞内氨基酸转运和雷帕霉素靶蛋白复合物 1（mTORC1）信号方面的进展揭示了溶质载体 38 家族 A 成员 9（SLC38A9），这是一种溶酶体转运蛋白，负责结合和转运几种必需氨基酸。在这里，我们展示了第一个来自斑马鱼的 SLC38A9 与精氨酸结合的晶体结构。在细胞质开放状态下，结合的精氨酸被 drSLC38A9 的跨膜螺旋 1（TM1）稳定在一个过渡状态中，该螺旋固定在 TM5 和 TM7 之间的凹槽中。这些锚定相互作用由 TM1 中的高度保守的 WNTMM 基序介导，该基序中的突变会使 drSLC38A9 丧失精氨酸转运能力。底物结合的潜在机制对于使 mTORC1 信号通路对氨基酸敏感以及维持溶酶体氨基酸动态平衡至关重要。这项研究为 SLC38 转运蛋白提供了一个原型模型的初步了解。
