2026-10-09 理化学研究所
細胞膜上におけるDOCK11の正のフィードバックによるCdc42増幅メカニズム
＜関連情報＞
- https://www.riken.jp/press/2026/20261009_1/index.html#wrapper
- https://www.pnas.org/doi/10.1073/pnas.2607665123
活性化Cdc42によるDOCK11の膜依存性正のフィードバック制御の構造的基盤 Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42
Tamao Hisano, Takehiro Shinoda, Mutsuko Kukimoto-Niino, +7 , and Mikako Shirouzu
Proceedings of the National Academy of Sciences Published:October 6, 2026
DOI:https://doi.org/10.1073/pnas.2607665123
Abstract
The guanine nucleotide exchange factor DOCK11 is widely expressed across tissues and activates Cdc42, a Rho family GTPase that regulates cytoskeletal remodeling and cell polarity. Loss-of-function mutations in DOCK11 have recently been linked to inborn errors of immunity. DOCK11 has also been implicated in facilitating hepatitis B virus infection in hepatocytes and has emerged as a potential target for therapeutic interventions. A positive feedback mechanism has been proposed for DOCK11-mediated Cdc42 activation; however, the structural basis for this regulation has remained unclear. Here we report the cryoelectron microscopy structures of full-length DOCK11 as an apo dimer, a binary complex with nucleotide-free Cdc42, and a ternary complex containing both nucleotide-free and activated Cdc42. DOCK11 predominantly adopts a U-shaped dimer that binds to nucleotide-free Cdc42 via the catalytic domain, whereas activated Cdc42 engages a distal site within the armadillo-repeat domain. Biochemical and cellular analyses demonstrate that binding of activated Cdc42 is critical for enhancing the membrane-dependent nucleotide exchange activity of DOCK11, promoting its localization to the plasma membrane, and facilitating intracellular activation of Cdc42. We also determined the structure of the membrane-bound ternary complex using membrane-coated grids. Strikingly, the ternary complex adopts an extended conformation that aligns multiple membrane-contact elements, revealing how activated Cdc42 stabilizes DOCK11 membrane binding for efficient exchange activity. Collectively, these findings provide a structural framework for the coordinated mechanism underlying membrane-dependent positive feedback in Rho GTPase signaling.
