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Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms [Biochemistry]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2018-09-18 , DOI: 10.1073/pnas.1811727115
Kuang Shen 1, 2, 3, 4, 5 , David M. Sabatini 1, 2, 3, 4, 5
Affiliation  

The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses a unique “locking” mechanism to stabilize its active (GTPRagA–RagCGDP) or inactive (GDPRagA–RagCGTP) nucleotide states. The Ragulator complex tethers the Rag heterodimer to the lysosomal surface, and the SLC38A9 transmembrane protein is a lysosomal arginine sensor that upon activation stimulates mTORC1 activity through the Rag GTPases. How Ragulator and SLC38A9 control the nucleotide loading state of the Rag GTPases remains incompletely understood. Here we find that Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state. Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Altogether, Ragulator and SLC38A9 act on the Rag GTPases to activate the mTORC1 pathway in response to nutrient sufficiency.



中文翻译:

Ragulator和SLC38A9通过非规范的GEF机制激活Rag GTPases [生物化学]

雷帕霉素复合物1(mTORC1)生长途径的机械靶标通过聚集在Rag GTPases上的各种传感器和调节剂检测营养,后者形成与RagC或RagD紧密结合的RagA或RagB组成的异二聚体,并控制mTORC1的亚细胞定位。Rag异二聚体使用独特的“锁定”机制来稳定其活跃的(GTP RagA–RagC GDP)或非活跃的(GDP RagA–RagC GTP))核苷酸状态。Ragulator复合物将Rag异二聚体拴在溶酶体表面,SLC38A9跨膜蛋白是一种溶酶体精氨酸传感器,在激活后会通过Rag GTPases刺激mTORC1活性。Ragulator和SLC38A9如何控制Rag GTPases的核苷酸加载状态的方法尚未完全了解。在这里,我们发现Ragulator和SLC38A9都是独特的鸟嘌呤交换因子(GEF),共同将Rag GTPases推向活跃状态。Ragulator触发从RagC释放GTP,从而解决了Rag GTPases的锁定未激活状态。精氨酸结合后,SLC38A9将RagA从GDP转换为GTP加载状态,因此激活了Rag GTPase异二聚体。共,

更新日期:2018-09-19
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