人类FLCN-FNIP2-Rag-Ragulator复合物的冷冻电镜结构获解析，这一成果由美国麻省理工学院David M. Sabatini、霍华德休斯医学研究所Zhiheng Yu等研究人员合作取得。该项研究成果2019年11月5日在线发表在《细胞》上。

研究人员使用冷冻电镜来确定了FLCN-FNIP2与Rag GTP酶和Ragulator形成复合物后的结构。FLCN-FNIP2采用带有两对异二聚结构域的扩展构象。Longin结构域异二聚体化并与Rag异二聚体的两个核苷酸结合结构域接触，而DENN结构域在结构的远端相互作用。生化分析表明，FLCN上的精氨酸是保守的催化型精氨酸指，研究人员将其结构解释为途中中间体。这些数据揭示了GAP与GTP酶相互作用的特征以及营养敏感型mTORC1途径关键组成部分的结构。

据介绍，mTORC1通过Rag GTP酶异源二聚体控制营养物质的代谢过程和分解代谢过程，该过程由多个上游蛋白质复合物调节。其中一种这样的调节者（FLCN-FNIP2）是RagC/D的GTP酶激活蛋白（GAP），但是，尽管它起着重要的作用，但如何激活Rag GTP酶异二聚体仍然未知。

附：英文原文

Title: Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex

Author: Kuang Shen, Kacper B. Rogala, Hui-Ting Chou, Rick K. Huang, Zhiheng Yu, David M. Sabatini

Issue&Volume: November 5, 2019

Abstract: mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. The Longin domains heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, while the DENN domains interact at the distal end of the structure. Biochemical analyses reveal a conserved arginine on FLCN as the catalytic arginine finger and lead us to interpret our structure as an on-pathway intermediate. These data reveal features of a GAP-GTPase interaction and the structure of a critical component of the nutrient-sensing mTORC1 pathway.

DOI: 10.1016/j.cell.2019.10.036

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31213-9