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Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation
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 exchan...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372576/ https://www.ncbi.nlm.nih.gov/pubmed/37463208 http://dx.doi.org/10.1073/pnas.2303750120 |
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author | Borchers, Ann-Christin Janz, Maren Schäfer, Jan-Hannes Moeller, Arne Kümmel, Daniel Paululat, Achim Ungermann, Christian Langemeyer, Lars |
author_facet | Borchers, Ann-Christin Janz, Maren Schäfer, Jan-Hannes Moeller, Arne Kümmel, Daniel Paululat, Achim Ungermann, Christian Langemeyer, Lars |
author_sort | Borchers, Ann-Christin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10372576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-103725762023-07-28 Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation Borchers, Ann-Christin Janz, Maren Schäfer, Jan-Hannes Moeller, Arne Kümmel, Daniel Paululat, Achim Ungermann, Christian Langemeyer, Lars Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-07-18 2023-07-25 /pmc/articles/PMC10372576/ /pubmed/37463208 http://dx.doi.org/10.1073/pnas.2303750120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Borchers, Ann-Christin Janz, Maren Schäfer, Jan-Hannes Moeller, Arne Kümmel, Daniel Paululat, Achim Ungermann, Christian Langemeyer, Lars Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation |
title | Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation |
title_full | Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation |
title_fullStr | Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation |
title_full_unstemmed | Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation |
title_short | Regulatory sites in the Mon1–Ccz1 complex control Rab5 to Rab7 transition and endosome maturation |
title_sort | regulatory sites in the mon1–ccz1 complex control rab5 to rab7 transition and endosome maturation |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372576/ https://www.ncbi.nlm.nih.gov/pubmed/37463208 http://dx.doi.org/10.1073/pnas.2303750120 |
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