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Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate

Wu, Xudong, Bradley, Michael J., Cai, Yiying, Kümmel, Daniel, De La Cruz, Enrique M., Barr, Francis A., Reinisch, Karin M.·2011·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1110415108
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Abstract

Rab GTPases are key regulators of membrane traffic pathways within eukaryotic cells. They are specifically activated by guanine nucleotide exchange factors (GEFs), which convert them from their “inactive” GDP-bound form to the “active” GTP-bound form. In higher eukaryotes, proteins containing DENN-domains comprise a major GEF family. Here we describe at 2.1-Å resolution the first structure of a DENN-domain protein, DENND1B-S, complexed with its substrate Rab35, providing novel insights as to how DENN-domain GEFs interact with and activate Rabs. DENND1B-S is bi-lobed, and interactions with Rab35 are through conserved surfaces in both lobes. Rab35 binds via switch regions I and II, around the nucleotide-binding pocket. Positional shifts in Rab residues required for nucleotide binding may lower its affinity for bound GDP, and a conformational change in switch I, which makes the nucleotide-binding pocket more solvent accessible, likely also facilitates exchange.

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Crossref · 10.1073/pnas.1110415108

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  • The AFM model reveals that DENND10 consists of two closely packed domains, the N-terminal domain and the C-terminal domain, similar to the crystal structure of the DENN domain from DENND13.

    “The AFM model reveals that DENND10 consists of two closely packed domains, the N-terminal domain (NTD) and the C-terminal domain (CTD), similar to the crystal structure of the DENN domain from DENND135 (Fig. 6A, Extended Data Fig. 6D).”

    From Structural organization of the retriever–CCC endosomal recycling complex (2024) · cites this paper as [35]

    The Results and Discussion (page unavailable) describe a crystal structure with an N-terminal lobe and a C-terminal lobe, supporting the structural comparison. But the structure is of DENND1B, not DENND13 as stated in the supplied claim. The source does not report the citing authors’ DENND10 AFM model. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The only structure of a DENN domain-RAB complex is of DENND1B and RAB35.

    “the only structure of a DENN domain-RAB complex is of DENND1B and RAB35.70”

    From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [70]

    The Abstract describes a structure of DENND1B-S complexed with Rab35 and calls it the first structure of a DENN-domain protein bound to its substrate. It does not establish the citing sentence’s stronger claim that this is the only DENN-domain–Rab complex structure. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Only one crystal structure of a DENN domain in complex with a RAB GEF substrate has been determined.

    “Only one crystal structure of a DENN domain in complex with a RAB GEF substrate has been determined,70”

    From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [70]

    The Abstract calls the DENND1B-S–Rab35 complex the first structure of a DENN-domain protein bound to its Rab substrate, and Results and Discussion describes the crystals obtained. That supports the existence of the structure and its priority in 2011, but does not establish that it remained the only such structure when the citing sentence was written. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Citations

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Research works printed but not linked: 36

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Metadata

Authors
Wu, X., Bradley, M. J., Cai, Y., Kümmel, D., De La Cruz, E. M., Barr, F. A., & Reinisch, K. M.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2011-11-07
Volume
108
Issue
46
Pages
18672-18677
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1110415108
Cited by
115
References
0
Language
en

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