がん関連タンパク質「AKT」が細胞膜に結合・安定化する新たな仕組みを解明 －脂質認識PHドメインとキナーゼドメインの協働を分子シミュレーションと1分子観察で実証－

2026-10-13 慶應義塾大学,岐阜大学,国立がん研究センター

図1：AKTが脂質膜に結合した状態の分子動力学シミュレーション PHドメイン（水色）とKD（橙色）が脂質膜中のPIP3と相互作用．

＜関連情報＞

• https://www.keio.ac.jp/ja/press-release/20261013-press-01/
• https://www.keio.ac.jp/fixed-files/20261013-press-01-f7iarojt.pdf
• https://pubs.acs.org/jacsat/article-abstract/doi/10.1021/jacs.6c13162/5441790/Cooperative-Membrane-Recognition-by-Lipid-Sensing

脂質感知ドメインとキナーゼドメインによる協調的な膜認識がAKTの膜結合状態を形成する Cooperative Membrane Recognition by Lipid-Sensing and Kinase Domains Shapes Membrane-Bound States of AKT

Yuki Nakagaki;Toshiki Mori;Kenichi G. N. Suzuki;Eiji Yamamoto
Journal of the American Chemical Society  Published:September 29, 2026
DOI:https://doi.org/10.1021/jacs.6c13162

Abstract

The PI3K/AKT signaling pathway is triggered by the recruitment of AKT to cellular membranes. Although AKT is a multidomain serine/threonine kinase composed of an N-terminal pleckstrin homology (PH) domain and a C-terminal kinase domain (KD), how these domains cooperate to regulate AKT activation on membranes remains unclear at the molecular level. Here, using molecular dynamics simulations of full-length AKT on phosphatidylinositol (3,4,5)-trisphosphate (PIP₃)-containing lipid bilayers, we identify four distinct membrane-binding modes that differ in the orientations and membrane contacts of the PH domain and KD. In addition to PIP₃ binding to the PH domain, we observed specific PIP₃ interactions with basic residues in the KD. In the most stable mode, PIP₃ interacts with both the canonical and a secondary binding site in the PH domain, while the KD adopts an orientation in which the activation loop phosphorylation site is exposed to the solvent. The populations of these binding modes depend on the PIP₃ concentration in the membrane, leading to changes in the preferred orientation of AKT. Live-cell single-molecule imaging further supports distinct but cooperative roles of the PH domain and KD in membrane recruitment: the PH domain primarily promotes membrane association, whereas the KD enhances recruitment efficiency and stabilizes longer-residence membrane-bound states. These findings suggest that AKT membrane recruitment is governed by cooperative contributions from both the PH domain and the KD, providing molecular insight into how AKT is positioned and stabilized on PIP₃-containing membranes.