Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42.
4 affiliations
- 1Laboratory for Protein Functional and Structural Biology, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Kanagawa, Japan.
- 2Core Facility Administration, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8511, Aichi, Japan.
- 3Mass Spectrometry Analysis Team, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Hyogo, Japan.
- 4Structural Life Science and Cell Biology Collaboration Team, RIKEN Center for Biosystems Dynamics Research, Yokohama 230-0045, Kanagawa, Japan.
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.
Related
- Structural basis of isoform-specific cAMP regulation and autoinhibition in hyperpolarization-activated cyclic nucleotide-gated channels
- Energy Landscape Sampling Reveals Ligand-Dependent Structural Dynamics of the Protease-Activated Receptor 1.
- Saponins induce lipid-dependent structural heterogeneity and modulate membrane organization in phospholipid bilayers
- Small-Conductance Ca2+-Activated K+ Channels and Their Regulation of Excitability of Autonomic Neurons
- Structural basis of voltage gating in a partially activated K+ channel
BibTeX
@article{hisano2026structural,
title = {{Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42.}},
author = {Tamao Hisano and Takehiro Shinoda and Mutsuko Kukimoto-Niino and Kazushige Katsura and Ryohei Kondo and Yoshiko Ishizuka-Katsura and Yukako Miyata-Yabuki and Kazuharu Hanada and Reiko Nakagawa and Akihiko Nishikimi and Mikako Shirouzu},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2607665123},
url = {https://europepmc.org/article/MED/42837459},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42.
AU - Tamao Hisano
AU - Takehiro Shinoda
AU - Mutsuko Kukimoto-Niino
AU - Kazushige Katsura
AU - Ryohei Kondo
AU - Yoshiko Ishizuka-Katsura
AU - Yukako Miyata-Yabuki
AU - Kazuharu Hanada
AU - Reiko Nakagawa
AU - Akihiko Nishikimi
AU - Mikako Shirouzu
PY - 2026
DA - 2026/10/06
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2607665123
UR - https://europepmc.org/article/MED/42837459
AB - 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.
SN - 0027-8424
SN - 1091-6490
ER -