Crystal structure of the Gtr1p-Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation
Crystal structure of the Gtr1p-Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation
复制标题
Gtr1p-Gtr2p 复合物的晶体结构揭示了氨基酸诱导的 TORC1 激活的新见解
DOI：
10.1101/gad.16968011
复制
发表时间：
2011-08-15
影响因子：
10.5
通讯作者：
Xu, Yanhui
中科院分区：
文献类型：
--
作者：
Gong, Rui;Li, Li;Xu, Yanhui
雷帕霉素靶蛋白（TOR）复合物1 （TORC1）是响应多种信号的中枢细胞生长调节剂。Rag gtpase通过与raptor的直接相互作用和TORC1复合体向溶酶体的募集，在将氨基酸信号传递到TORC1激活中发挥重要作用。在这里，我们展示了Gtr1p-Gtr2p配合物的晶体结构，这是来自酿酒酵母的Rag同源物，分辨率为2.8埃。异二聚体gtpase显示出伪双重对称组织。Gtr1p-Gtr2p的人类同源物RagA-RagC的结构导向功能分析表明，G结构域（n端GTPase结构域）和二聚化对猛禽结合都很重要。特别是，RagA中G结构域的开关区域对于与raptor的相互作用以及TORC1的激活是必不可少的。RagA-RagC的二聚c端结构域与MP1/p14具有显著的结构相似性，MP1/p14与溶酶体膜蛋白p18形成复合体，并直接与p18相互作用，从而将mTORC1招募到溶酶体中，由Rheb激活。我们的研究结果揭示了Rag GTPases在TORC1激活和氨基酸信号传导中的机制的结构模型。
The target of rapamycin (TOR) complex 1 (TORC1) is a central cell growth regulator in response to a wide array of signals. The Rag GTPases play an essential role in relaying amino acid signals to TORC1 activation through direct interaction with raptor and recruitment of the TORC1 complex to lysosomes. Here we present the crystal structure of the Gtr1p-Gtr2p complex, the Rag homologs from Saccharomyces cerevisiae, at 2.8 angstrom resolution. The heterodimeric GTPases reveal a pseudo-twofold symmetric organization. Structure-guided functional analyses of RagA-RagC, the human homologs of Gtr1p-Gtr2p, show that both G domains (N-terminal GTPase domains) and dimerization are important for raptor binding. In particular, the switch regions of the G domain in RagA are indispensible for interaction with raptor, and hence TORC1 activation. The dimerized C-terminal domains of RagA-RagC display a remarkable structural similarity to MP1/p14, which is in a complex with lysosome membrane protein p18, and directly interact with p18, therefore recruiting mTORC1 to the lysosome for activation by Rheb. Our results reveal a structural model for the mechanism of the Rag GTPases in TORC1 activation and amino acid signaling.