22VG

Cryo-EM structure of DOCK11 complexed with Cdc42(G15A) and Cdc42(Q61L)-GTP in the membrane-bound state

This is a non-PDB format compatible entry.

Summary for 22VG

• Entry DOI: 10.2210/pdb22vg/pdb
• Related: 22VD 22VE 22VF
• EMDB information: 68714
• Descriptor: Dedicator of cytokinesis protein 11, Cell division control protein 42 homolog, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: signaling protein, rhogef, ternary complex, membrane-bound state
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 563731.32

Authors

Hisano, T.,Shinoda, T.,Kukimoto-Niino, M.,Katsura, K.,Shirouzu, M. (deposition date: 2026-01-25, release date: 2026-10-21)

Primary citation

Hisano, T.,Shinoda, T.,Kukimoto-Niino, M.,Katsura, K.,Kondo, R.,Ishizuka-Katsura, Y.,Miyata-Yabuki, Y.,Hanada, K.,Nakagawa, R.,Nishikimi, A.,Shirouzu, M.
Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42.
Proc.Natl.Acad.Sci.USA, 123:e2607665123-e2607665123, 2026

PubMed 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.

PubMed: 42837459
DOI: 10.1073/pnas.2607665123

Experimental method

ELECTRON MICROSCOPY (6.07 Å)