{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory for Protein Functional and Structural Biology, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Kanagawa, Japan.",
    "Core Facility Administration, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8511, Aichi, Japan.",
    "Mass Spectrometry Analysis Team, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Hyogo, Japan.",
    "Structural Life Science and Cell Biology Collaboration Team, RIKEN Center for Biosystems Dynamics Research, Yokohama 230-0045, Kanagawa, Japan."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Tamao Hisano",
      "orcid": "0000-0002-5832-8442"
    },
    {
      "affs": [
        0
      ],
      "name": "Takehiro Shinoda",
      "orcid": "0000-0003-0297-2471"
    },
    {
      "affs": [
        0
      ],
      "name": "Mutsuko Kukimoto-Niino",
      "orcid": "0000-0002-4178-1611"
    },
    {
      "affs": [
        0
      ],
      "name": "Kazushige Katsura",
      "orcid": "0000-0002-4333-0224"
    },
    {
      "affs": [
        1
      ],
      "name": "Ryohei Kondo"
    },
    {
      "affs": [
        0
      ],
      "name": "Yoshiko Ishizuka-Katsura"
    },
    {
      "affs": [
        0
      ],
      "name": "Yukako Miyata-Yabuki",
      "orcid": "0000-0003-2203-372X"
    },
    {
      "affs": [
        0
      ],
      "name": "Kazuharu Hanada"
    },
    {
      "affs": [
        2
      ],
      "name": "Reiko Nakagawa",
      "orcid": "0000-0002-6178-2945"
    },
    {
      "affs": [
        1
      ],
      "name": "Akihiko Nishikimi",
      "orcid": "0000-0001-9497-7557"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Mikako Shirouzu",
      "orcid": "0000-0002-7997-2149"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/av4z29zj917y8.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2607665123",
  "fulltext_url": "https://europepmc.org/articles/PMC13663769",
  "id": "av4z29zj917y8",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://europepmc.org/article/MED/42837459",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Kinase Regulation and GTPase Signaling"
    ]
  ],
  "openalex": "W7220684044",
  "pdf_url": "https://europepmc.org/articles/PMC13663769?pdf=render",
  "pmcid": "PMC13663769",
  "pmid": "42837459",
  "published": "2026-10-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/av4z29zj917y8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:03Z",
      "native_id": "MED:42837459",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42837459"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Kinase Regulation and GTPase Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42.",
  "title_text": "Structural basis for membrane-dependent positive feedback regulation of DOCK11 by activated Cdc42.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:03Z",
  "url": "https://research.draconitic.com/paper/av4z29zj917y8",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}