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PreprintCited by 43Cellular transport and secretionProtein Kinase Regulation and GTPase SignalingAutophagy in Disease and Therapy

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Regulatory sites in the Mon1-Ccz1 complex control Rab5 to Rab7 transition and endosome maturation

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Borchers, Ann-Christin, Janz, Maren, Schäfer, Jan-Hannes, Moeller, Arne, Kümmel, Daniel, Paululat, Achim, Ungermann, Christian, Langemeyer, Lars·2023·Proceedings of the National Academy of Sciences
DOI 10.1101/2023.03.01.530579PMC PMC10372576

Preprint — published as 10.1073/pnas.2303750120 · Paper page

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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-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 a shift from Rab5 to more Rab7 positive structures in Drosophila nephrocytes and yeast, suggesting 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 Rab-conversion and organelle maturation along the endomembrane system. Summary: Transport of proteins via the endolysosomal pathway requires Rab5 on early endosomes, which is replaced by Rab7 on late endosomes. Here, we identify distinct regulatory sites in the Rab7 activator, the Mon1-Ccz1 complex, shedding light on the regulation of Rab5 to Rab7 transition.

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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
openRxiv
Published
2023-03-02
Volume
120
Issue
30
Pages
e2303750120-e2303750120
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2023.03.01.530579
PMC
PMC10372576
OpenAlex
W4384662305
Cited by
43
References
1
Citations by year
2026: 17 · 2025: 13 · 2024: 12 · 2023: 1
FWCI
6.20
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
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 (SFB 944, SFB 944 and SFB 1557, SFB1557, UN111/9-2 PA517/12-2)
  • Universität Osnabrück
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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