9ED8

Intermediate state of mTOR on membrane

9ED8 の概要

• エントリーDOI: 10.2210/pdb9ed8/pdb
• EMDBエントリー: 47940
• 分子名称: Serine/threonine-protein kinase mTOR, Target of rapamycin complex subunit LST8, GTP-binding protein Rheb, ... (7 entities in total)
• 機能のキーワード: mtorc1, cell growth, signaling protein, membrane
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 347417.29

構造登録者

Cui, Z.,Hurley, J. (登録日: 2024-11-16, 公開日: 2025-09-10, 最終更新日: 2025-10-01)

主引用文献

Cui, Z.,Esposito, A.,Napolitano, G.,Ballabio, A.,Hurley, J.H.
Structural basis for mTORC1 activation on the lysosomal membrane.
Nature, 2025

PubMed Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB). Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Cryo-electron microscopy showed that RAPTOR and mTOR interact directly with the membrane. Full engagement of the membrane anchors is required for optimal alignment of the catalytic residues in the mTOR kinase active site. Converging signals from GFs and nutrients drive mTORC1 recruitment to and activation on lysosomal membrane in a four-step process, consisting of (1) RAG-Ragulator-driven recruitment to within ~100 Å of the lysosomal membrane; (2) RHEB-driven recruitment to within ~40 Å; (3) RAPTOR-membrane engagement and intermediate enzyme activation; and (4) mTOR-membrane engagement and full enzyme activation. RHEB and membrane engagement combined leads to full catalytic activation and structurally explains GF and nutrient signal integration at the lysosome.

PubMed: 40963021
DOI: 10.1038/s41586-025-09545-3

実験手法

ELECTRON MICROSCOPY (3.61 Å)