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...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2023-07, Vol.120 (30), p.e2303750120-e2303750120 |
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| creator | Borchers, Ann-Christin Janz, Maren Schäfer, Jan-Hannes Moeller, Arne Kümmel, Daniel Paululat, Achim Ungermann, Christian Langemeyer, Lars |
| 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
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. |
| doi_str_mv | 10.1073/pnas.2303750120 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2303750120</identifier><identifier>PMID: 37463208</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Binding sites ; Biological Sciences ; Drosophila - metabolism ; Drosophila Proteins - genetics ; Drosophila Proteins - metabolism ; Endosomes ; Endosomes - metabolism ; Exchanging ; Guanine nucleotide exchange factor ; Guanine Nucleotide Exchange Factors - metabolism ; Maturation ; Membranes ; Nucleotides ; Protein Transport ; rab GTP-Binding Proteins - metabolism ; rab5 GTP-Binding Proteins - genetics ; rab5 GTP-Binding Proteins - metabolism ; Saccharomyces cerevisiae - metabolism ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Vesicular Transport Proteins - metabolism ; Yeasts</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2023-07, Vol.120 (30), p.e2303750120-e2303750120</ispartof><rights>Copyright National Academy of Sciences Jul 25, 2023</rights><rights>Copyright © 2023 the Author(s). Published by PNAS. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-7814550e7eef7d6bed0d4a1d97dc043c70bb0d10bce16aff5806eddbbeef0c173</citedby><cites>FETCH-LOGICAL-c422t-7814550e7eef7d6bed0d4a1d97dc043c70bb0d10bce16aff5806eddbbeef0c173</cites><orcidid>0000-0002-4309-0910 ; 0000-0002-8845-6859 ; 0000-0002-0348-9046 ; 0000-0003-2466-0129 ; 0000-0003-4331-8695 ; 0000-0001-8163-1629 ; 0000-0003-3950-5914</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372576/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372576/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37463208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Borchers, Ann-Christin</creatorcontrib><creatorcontrib>Janz, Maren</creatorcontrib><creatorcontrib>Schäfer, Jan-Hannes</creatorcontrib><creatorcontrib>Moeller, Arne</creatorcontrib><creatorcontrib>Kümmel, Daniel</creatorcontrib><creatorcontrib>Paululat, Achim</creatorcontrib><creatorcontrib>Ungermann, Christian</creatorcontrib><creatorcontrib>Langemeyer, Lars</creatorcontrib><title>Regulatory sites in the Mon1-Ccz1 complex control Rab5 to Rab7 transition and endosome maturation</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><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
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. 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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
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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>37463208</pmid><doi>10.1073/pnas.2303750120</doi><orcidid>https://orcid.org/0000-0002-4309-0910</orcidid><orcidid>https://orcid.org/0000-0002-8845-6859</orcidid><orcidid>https://orcid.org/0000-0002-0348-9046</orcidid><orcidid>https://orcid.org/0000-0003-2466-0129</orcidid><orcidid>https://orcid.org/0000-0003-4331-8695</orcidid><orcidid>https://orcid.org/0000-0001-8163-1629</orcidid><orcidid>https://orcid.org/0000-0003-3950-5914</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Binding sites Biological Sciences Drosophila - metabolism Drosophila Proteins - genetics Drosophila Proteins - metabolism Endosomes Endosomes - metabolism Exchanging Guanine nucleotide exchange factor Guanine Nucleotide Exchange Factors - metabolism Maturation Membranes Nucleotides Protein Transport rab GTP-Binding Proteins - metabolism rab5 GTP-Binding Proteins - genetics rab5 GTP-Binding Proteins - metabolism Saccharomyces cerevisiae - metabolism Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Vesicular Transport Proteins - metabolism Yeasts |
| title | Regulatory sites in the Mon1-Ccz1 complex control Rab5 to Rab7 transition and endosome maturation |
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