---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
PlanS_conform: '1'
_id: '20351'
abstract:
- lang: eng
  text: Rab GTPases organize intracellular trafficking and provide identity to organelles.
    Their spatiotemporal activation by guanine nucleotide exchange factors (GEFs)
    is tightly controlled to ensure fidelity. Our structural and functional comparison
    of the tri-longin domain RabGEFs Mon1-Ccz1 and Fuzzy-Inturned reveals the molecular
    basis for their target specificity. Both complexes rely on a conserved sequence
    motif of their substrate GTPases for the catalytic mechanism, while secondary
    interactions allow discrimination between targets. We also find that dimeric Mon1-Ccz1
    from fungi and the metazoan homologs with the additional third subunit RMC1/Bulli
    bind membranes through electrostatic interactions via distinct interfaces. Protein-lipid
    interaction studies and functional characterization in flies reveal an essential
    function of RMC1/Bulli as mediator of GEF complex membrane recruitment. In the
    case of Fuzzy-Inturned, reconstitution experiments demonstrate that the BAR (Bin-Amphiphysin-Rvs)
    domain protein CiBAR1 can support membrane recruitment of the GEF. Collectively,
    our study demonstrates the molecular basis for the adaptation of TLD-RabGEFs to
    different cellular functions.
acknowledgement: 'We thank A.-M. Lawrence-Dörner and B. Berkenfeld for technical assistance
  and the members of the Kümmel Lab for constructive feedback. We are grateful to
  C. Ungermann and L. Langemeyer for insightful discussions and to F. Barr for providing
  plasmids encoding Fuzzy, Inturned, Rab23, and Rsg1. The template clone Flag-ciBAR1
  was a gift from K.-I. Takemaru (Addgene, plasmid #200440). We thank the Bloomington
  Drosophila Stock center (BDSC) and DSHB for providing fly stocks and antibodies.
  This work was supported by the German Research Foundation (DFG) through the grants
  SFB1557-P10 (D.K.), SFB1557-P11 (A.M.), and SFB1577-P6, PA517/12-2, PA517/14-1,
  PA517/15-1, and PA517/16-1 (A.P.). Cryo-EM data were collected at the infrastructure
  of the University of Osnabrück, funded by the DFG (project number 455249646). J.-H.S.
  was supported by the Friedrich-Ebert Foundation. M.L. acknowledges funding from
  the European Research Council (ERC) under the European Union’s Horizon 2020 research
  and innovation program (grant agreement number 101045340).'
article_processing_charge: Yes
article_type: original
author:
- first_name: Stephan
  full_name: Wilmes, Stephan
  last_name: Wilmes
- first_name: Jesse
  full_name: Tönjes, Jesse
  last_name: Tönjes
- first_name: Maik
  full_name: Drechsler, Maik
  last_name: Drechsler
- first_name: Anita
  full_name: Ruf, Anita
  last_name: Ruf
- first_name: Jan Hannes
  full_name: Schäfer, Jan Hannes
  last_name: Schäfer
- first_name: Anna
  full_name: Lürick, Anna
  last_name: Lürick
- first_name: Dovile
  full_name: Januliene, Dovile
  last_name: Januliene
- first_name: Steven
  full_name: Apelt, Steven
  last_name: Apelt
- first_name: Daniele
  full_name: Di Iorio, Daniele
  last_name: Di Iorio
- first_name: Seraphine V.
  full_name: Wegner, Seraphine V.
  last_name: Wegner
- first_name: Martin
  full_name: Loose, Martin
  id: 462D4284-F248-11E8-B48F-1D18A9856A87
  last_name: Loose
  orcid: 0000-0001-7309-9724
- first_name: Arne
  full_name: Moeller, Arne
  last_name: Moeller
- first_name: Achim
  full_name: Paululat, Achim
  last_name: Paululat
- first_name: Daniel
  full_name: Kümmel, Daniel
  last_name: Kümmel
citation:
  ama: Wilmes S, Tönjes J, Drechsler M, et al. Mechanistic adaptation of the metazoan
    RabGEFs Mon1-Ccz1 and Fuzzy-Inturned. <i>Science Advances</i>. 2025;11(35):eadx2893.
    doi:<a href="https://doi.org/10.1126/sciadv.adx2893">10.1126/sciadv.adx2893</a>
  apa: Wilmes, S., Tönjes, J., Drechsler, M., Ruf, A., Schäfer, J. H., Lürick, A.,
    … Kümmel, D. (2025). Mechanistic adaptation of the metazoan RabGEFs Mon1-Ccz1
    and Fuzzy-Inturned. <i>Science Advances</i>. AAAS. <a href="https://doi.org/10.1126/sciadv.adx2893">https://doi.org/10.1126/sciadv.adx2893</a>
  chicago: Wilmes, Stephan, Jesse Tönjes, Maik Drechsler, Anita Ruf, Jan Hannes Schäfer,
    Anna Lürick, Dovile Januliene, et al. “Mechanistic Adaptation of the Metazoan
    RabGEFs Mon1-Ccz1 and Fuzzy-Inturned.” <i>Science Advances</i>. AAAS, 2025. <a
    href="https://doi.org/10.1126/sciadv.adx2893">https://doi.org/10.1126/sciadv.adx2893</a>.
  ieee: S. Wilmes <i>et al.</i>, “Mechanistic adaptation of the metazoan RabGEFs Mon1-Ccz1
    and Fuzzy-Inturned,” <i>Science Advances</i>, vol. 11, no. 35. AAAS, p. eadx2893,
    2025.
  ista: Wilmes S, Tönjes J, Drechsler M, Ruf A, Schäfer JH, Lürick A, Januliene D,
    Apelt S, Di Iorio D, Wegner SV, Loose M, Moeller A, Paululat A, Kümmel D. 2025.
    Mechanistic adaptation of the metazoan RabGEFs Mon1-Ccz1 and Fuzzy-Inturned. Science
    Advances. 11(35), eadx2893.
  mla: Wilmes, Stephan, et al. “Mechanistic Adaptation of the Metazoan RabGEFs Mon1-Ccz1
    and Fuzzy-Inturned.” <i>Science Advances</i>, vol. 11, no. 35, AAAS, 2025, p.
    eadx2893, doi:<a href="https://doi.org/10.1126/sciadv.adx2893">10.1126/sciadv.adx2893</a>.
  short: S. Wilmes, J. Tönjes, M. Drechsler, A. Ruf, J.H. Schäfer, A. Lürick, D. Januliene,
    S. Apelt, D. Di Iorio, S.V. Wegner, M. Loose, A. Moeller, A. Paululat, D. Kümmel,
    Science Advances 11 (2025) eadx2893.
date_created: 2025-09-14T22:01:32Z
date_published: 2025-08-29T00:00:00Z
date_updated: 2025-09-30T14:40:27Z
day: '29'
ddc:
- '570'
department:
- _id: MaLo
doi: 10.1126/sciadv.adx2893
external_id:
  isi:
  - '001559806100033'
  pmid:
  - '40864718'
file:
- access_level: open_access
  checksum: a3de801f3c6c1deadd7099d965db799a
  content_type: application/pdf
  creator: dernst
  date_created: 2025-09-15T07:23:12Z
  date_updated: 2025-09-15T07:23:12Z
  file_id: '20355'
  file_name: 2025_ScienceAdvance_Wilmes.pdf
  file_size: 3434827
  relation: main_file
  success: 1
file_date_updated: 2025-09-15T07:23:12Z
has_accepted_license: '1'
intvolume: '        11'
isi: 1
issue: '35'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '08'
oa: 1
oa_version: Published Version
page: eadx2893
pmid: 1
project:
- _id: bd6ae2ca-d553-11ed-ba76-a4aa239da5ee
  grant_number: '101045340'
  name: Synthetic and structural biology of Rab GTPase networks
publication: Science Advances
publication_identifier:
  eissn:
  - 2375-2548
publication_status: published
publisher: AAAS
quality_controlled: '1'
scopus_import: '1'
status: public
title: Mechanistic adaptation of the metazoan RabGEFs Mon1-Ccz1 and Fuzzy-Inturned
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 11
year: '2025'
...