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Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation
Open accessPublished version of a preprint
Abstract
Maturation from early to late endosomes depends on the exchange of their marker proteins Rab5 to Rab7. This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1–Ccz1. Efficient GEF activity of this complex on membranes depends on Rab5, thus driving Rab–GTPase exchange on endosomes. However, molecular details on the role of Rab5 in Mon1–Ccz1 activation are unclear. Here, we identify key features in Mon1 involved in GEF regulation. We show that the intrinsically disordered N-terminal domain of Mon1 autoinhibits Rab5-dependent GEF activity on membranes. Consequently, Mon1 truncations result in higher GEF activity in vitro and alterations in early endosomal structures in Drosophila nephrocytes. A shift from Rab5 to more Rab7-positive structures in yeast suggests faster endosomal maturation. Using modeling, we further identify a conserved Rab5-binding site in Mon1. Mutations impairing Rab5 interaction result in poor GEF activity on membranes and growth defects in vivo. Our analysis provides a framework to understand the mechanism of Ras-related in brain (Rab) conversion and organelle maturation along the endomembrane system.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Varadi, M., Anyango, S., Deshpande, M., Nair, S., Natassia, C., Yordanova, G., Yuan, D., Stroe, O., Wood, G., Laydon, A., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkab1061 · Cited by 7,850
Protein complex prediction with AlphaFold-Multimer
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Metadata
- Authors
- Borchers, A.-C., Janz, M., Schäfer, J.-H., Moeller, A., Kümmel, D., Paululat, A., Ungermann, C., & Langemeyer, L.
- Affiliations
- Osnabrück University (DE)
- University of Münster (DE)
- Corresponding author
- Ungermann, Christian
- Langemeyer, Lars
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2023-07-18
- Volume
- 120
- Issue
- 30
- Pages
- e2303750120-e2303750120
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC10372576
- OpenAlex
- W4384662305
- Cited by
- 43
- References
- 3
- Citations by year
- 2026: 17 · 2025: 13 · 2024: 12 · 2023: 1
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (UN111/9-2 PA517/12-2, SFB 944, SFB 1557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- Rab5, Rab7, guanine nucleotide exchange factor, endosome maturation, intrinsically disordered proteins, autoinhibition, yeast, endomembrane system
- MeSH terms
- Animals, Drosophila, Endosomes, Saccharomyces cerevisiae, Guanine Nucleotide Exchange Factors, rab GTP-Binding Proteins, rab5 GTP-Binding Proteins, Protein Transport, Saccharomyces cerevisiae Proteins, Drosophila Proteins, Vesicular Transport Proteins
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