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Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli

The endosomal system of eukaryotic cells represents a central sorting and recycling compartment linked to metabolic signaling and the regulation of cell growth. Tightly controlled activation of Rab GTPases is required to establish the different domains of endosomes and lysosomes. In metazoans, Rab7...

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Autores principales: Herrmann, Eric, Schäfer, Jan-Hannes, Wilmes, Stephan, Ungermann, Christian, Moeller, Arne, Kümmel, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193976/
https://www.ncbi.nlm.nih.gov/pubmed/37155863
http://dx.doi.org/10.1073/pnas.2301908120
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author Herrmann, Eric
Schäfer, Jan-Hannes
Wilmes, Stephan
Ungermann, Christian
Moeller, Arne
Kümmel, Daniel
author_facet Herrmann, Eric
Schäfer, Jan-Hannes
Wilmes, Stephan
Ungermann, Christian
Moeller, Arne
Kümmel, Daniel
author_sort Herrmann, Eric
collection PubMed
description The endosomal system of eukaryotic cells represents a central sorting and recycling compartment linked to metabolic signaling and the regulation of cell growth. Tightly controlled activation of Rab GTPases is required to establish the different domains of endosomes and lysosomes. In metazoans, Rab7 controls endosomal maturation, autophagy, and lysosomal function. It is activated by the guanine nucleotide exchange factor (GEF) complex Mon1–Ccz1–Bulli (MCBulli) of the tri-longin domain (TLD) family. While the Mon1 and Ccz1 subunits have been shown to constitute the active site of the complex, the role of Bulli remains elusive. We here present the cryo-electron microscopy (cryo-EM) structure of MCBulli at 3.2 Å resolution. Bulli associates as a leg-like extension at the periphery of the Mon1 and Ccz1 heterodimers, consistent with earlier reports that Bulli does not impact the activity of the complex or the interactions with recruiter and substrate GTPases. While MCBulli shows structural homology to the related ciliogenesis and planar cell polarity effector (Fuzzy–Inturned–Wdpcp) complex, the interaction of the TLD core subunits Mon1-Ccz1 and Fuzzy–Inturned with Bulli and Wdpcp, respectively, is remarkably different. The variations in the overall architecture suggest divergent functions of the Bulli and Wdpcp subunits. Based on our structural analysis, Bulli likely serves as a recruitment platform for additional regulators of endolysosomal trafficking to sites of Rab7 activation.
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spelling pubmed-101939762023-05-19 Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli Herrmann, Eric Schäfer, Jan-Hannes Wilmes, Stephan Ungermann, Christian Moeller, Arne Kümmel, Daniel Proc Natl Acad Sci U S A Biological Sciences The endosomal system of eukaryotic cells represents a central sorting and recycling compartment linked to metabolic signaling and the regulation of cell growth. Tightly controlled activation of Rab GTPases is required to establish the different domains of endosomes and lysosomes. In metazoans, Rab7 controls endosomal maturation, autophagy, and lysosomal function. It is activated by the guanine nucleotide exchange factor (GEF) complex Mon1–Ccz1–Bulli (MCBulli) of the tri-longin domain (TLD) family. While the Mon1 and Ccz1 subunits have been shown to constitute the active site of the complex, the role of Bulli remains elusive. We here present the cryo-electron microscopy (cryo-EM) structure of MCBulli at 3.2 Å resolution. Bulli associates as a leg-like extension at the periphery of the Mon1 and Ccz1 heterodimers, consistent with earlier reports that Bulli does not impact the activity of the complex or the interactions with recruiter and substrate GTPases. While MCBulli shows structural homology to the related ciliogenesis and planar cell polarity effector (Fuzzy–Inturned–Wdpcp) complex, the interaction of the TLD core subunits Mon1-Ccz1 and Fuzzy–Inturned with Bulli and Wdpcp, respectively, is remarkably different. The variations in the overall architecture suggest divergent functions of the Bulli and Wdpcp subunits. Based on our structural analysis, Bulli likely serves as a recruitment platform for additional regulators of endolysosomal trafficking to sites of Rab7 activation. National Academy of Sciences 2023-05-08 2023-05-16 /pmc/articles/PMC10193976/ /pubmed/37155863 http://dx.doi.org/10.1073/pnas.2301908120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Herrmann, Eric
Schäfer, Jan-Hannes
Wilmes, Stephan
Ungermann, Christian
Moeller, Arne
Kümmel, Daniel
Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli
title Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli
title_full Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli
title_fullStr Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli
title_full_unstemmed Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli
title_short Structure of the metazoan Rab7 GEF complex Mon1–Ccz1–Bulli
title_sort structure of the metazoan rab7 gef complex mon1–ccz1–bulli
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193976/
https://www.ncbi.nlm.nih.gov/pubmed/37155863
http://dx.doi.org/10.1073/pnas.2301908120
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