{"type":"journal_article","isi":1,"publisher":"AAAS","day":"29","month":"08","department":[{"_id":"MaLo"}],"DOAJ_listed":"1","PlanS_conform":"1","has_accepted_license":"1","pmid":1,"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."}],"year":"2025","date_created":"2025-09-14T22:01:32Z","author":[{"last_name":"Wilmes","full_name":"Wilmes, Stephan","first_name":"Stephan"},{"last_name":"Tönjes","full_name":"Tönjes, Jesse","first_name":"Jesse"},{"last_name":"Drechsler","first_name":"Maik","full_name":"Drechsler, Maik"},{"last_name":"Ruf","first_name":"Anita","full_name":"Ruf, Anita"},{"full_name":"Schäfer, Jan Hannes","first_name":"Jan Hannes","last_name":"Schäfer"},{"last_name":"Lürick","full_name":"Lürick, Anna","first_name":"Anna"},{"full_name":"Januliene, Dovile","first_name":"Dovile","last_name":"Januliene"},{"last_name":"Apelt","full_name":"Apelt, Steven","first_name":"Steven"},{"last_name":"Di Iorio","first_name":"Daniele","full_name":"Di Iorio, Daniele"},{"full_name":"Wegner, Seraphine V.","first_name":"Seraphine V.","last_name":"Wegner"},{"id":"462D4284-F248-11E8-B48F-1D18A9856A87","last_name":"Loose","full_name":"Loose, Martin","orcid":"0000-0001-7309-9724","first_name":"Martin"},{"last_name":"Moeller","full_name":"Moeller, Arne","first_name":"Arne"},{"first_name":"Achim","full_name":"Paululat, Achim","last_name":"Paululat"},{"first_name":"Daniel","full_name":"Kümmel, Daniel","last_name":"Kümmel"}],"OA_place":"publisher","intvolume":"        11","_id":"20351","issue":"35","volume":11,"status":"public","publication":"Science Advances","OA_type":"gold","publication_status":"published","language":[{"iso":"eng"}],"quality_controlled":"1","tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"article_processing_charge":"Yes","license":"https://creativecommons.org/licenses/by/4.0/","file_date_updated":"2025-09-15T07:23:12Z","oa_version":"Published Version","external_id":{"isi":["001559806100033"],"pmid":["40864718"]},"page":"eadx2893","citation":{"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.","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>","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.","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>.","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.","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>."},"scopus_import":"1","date_updated":"2025-09-30T14:40:27Z","project":[{"_id":"bd6ae2ca-d553-11ed-ba76-a4aa239da5ee","name":"Synthetic and structural biology of Rab GTPase networks","grant_number":"101045340"}],"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).","title":"Mechanistic adaptation of the metazoan RabGEFs Mon1-Ccz1 and Fuzzy-Inturned","doi":"10.1126/sciadv.adx2893","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","publication_identifier":{"eissn":["2375-2548"]},"oa":1,"ddc":["570"],"file":[{"relation":"main_file","content_type":"application/pdf","creator":"dernst","access_level":"open_access","checksum":"a3de801f3c6c1deadd7099d965db799a","success":1,"date_updated":"2025-09-15T07:23:12Z","file_size":3434827,"date_created":"2025-09-15T07:23:12Z","file_name":"2025_ScienceAdvance_Wilmes.pdf","file_id":"20355"}],"date_published":"2025-08-29T00:00:00Z","article_type":"original"}