人間のGATOR1およびGATOR1-Rag GTPases複合体の構造

Kuang Shen^1,2,3,4, Rick K Huang⁵, Edward J Brignole^2,6

¹Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 455 Main Street, Cambridge, Massachusetts 02142, USA.

Nature

|March 29, 2018

まとめ

研究者は,Rag GTPasesを調節することで,GATOR1複合体の構造を明らかにし,栄養素感知におけるその役割を明らかにした. この発見により,mTORC1経路を制御する新しいメカニズムが明らかになりました.

科学分野:

細胞生物学
分子機構
信号変換

背景:

mTORC1経路を通じて細胞の成長を調節する.
DEPDC5,NPRL2,NPRL3を含むGATOR1複合体は,Rag GTPasesのGTPase活性化タンパク質 (GAP) として作用し,mTORC1を制御する.
GATOR1の分子機能と構造は,その独特のタンパク質成分のために不明のままでした.

研究の目的:

GATOR1複合体の分子構造とRag GTPasesとの相互作用を決定する.
Rag GTPasesとmTORC1のシグナリングをGATOR1が調節するメカニズムを解明する.
mTORC1経路における栄養素検出の構造的基礎を理解する.

主な方法:

GATOR1およびGATOR1- Rag GTPase複合体の構造を解明するために,冷凍電子顕微鏡 (cryo-EM) が使用されました.
相互作用と酵素活性を特徴付けるために生化学的分析が行われました.

主要な成果:

GATOR1コンプレックスは,中央の空洞を持つ拡張されたアーキテクチャを展示しています.
DEPDC5はRAGAと直接相互作用し,GTPの水解を阻害し,NPRL2- NPRL3は弱い相互作用によってGAPの活性を媒介する.
構造は,GATOR1とRag GTPasesの間の少なくとも2つの異なる結合モードを明らかにする.

結論:

この研究は,mTORC1経路の重要な構成要素であるGATOR1複合体の分子構造を明らかにした.
GAP (GATOR1) とその基質GTPase (Rag) の間の非正規の相互作用メカニズムが解明されました.
これらの発見は細胞が栄養素を感知し成長を制御する方法を洞察します

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