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Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex
Molecular Cell ( IF 14.5 ) Pub Date : 2017-11-05 , DOI: 10.1016/j.molcel.2017.10.016
Ming-Yuan Su , Kyle L. Morris , Do Jin Kim , Yangxue Fu , Rosalie Lawrence , Goran Stjepanovic , Roberto Zoncu , James H. Hurley

The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. The crystal structure of the five-subunit human Ragulator at 1.4 Å resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1. EM was used to reconstruct the assembly of the full-length RagAGTP:RagCGDP dimer bound to Ragulator at 16 Å resolution, revealing that the G-domains of the Rags project away from the Ragulator core. The combined structural model shows how Ragulator functions as a platform for the presentation of active Rags for mTORC1 recruitment, and might suggest an unconventional mechanism for Rag GEF activity.



中文翻译:

RagA / C-ragulator mTORC1激活复合物的混合结构

溶酶体膜是检测细胞营养水平的场所,细胞营养水平通过Rag GTPases和Ragulator复合体转导至mTORC1。确定了五亚基人类碎肉机在1.4分辨率下的晶体结构。Lamtor1会包裹其他四个子单元,以稳定装配。Lamtor2:Lamtor3二聚体堆叠在Lamtor4:Lamtor5上,以创建Rag绑定平台。氢-氘交换用于将Rag结合位点映射到Lamtor2:Lamtor3二聚体的外表面和Lamtor1的N端固有无序区域。EM用于重构全长RagA GTP:RagC GDP的装配二聚体以16Å的分辨率与Ragulator结合,表明Rags的G结构域远离Ragulator核心突出。组合的结构模型显示了Ragulator如何用作展示主动Rags募集mTORC1的平台,并可能暗示了Rag GEF活动的非常规机制。

更新日期:2017-11-05
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