Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42.

Authors

Tamao Hisano, Takehiro Shinoda, Mutsuko Kukimoto-Niino, Kazushige Katsura, Ryohei Kondo, Yoshiko Ishizuka-Katsura, Yukako Miyata-Yabuki, Kazuharu Hanada, Reiko Nakagawa, Akihiko Nishikimi, Mikako Shirouzu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 41. Pages e2607665123. Oct 13, 2026. Epub Oct 06, 2026.

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.

PMID:
42837459
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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