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 RagA^GTP:RagC^GDP 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.

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。