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

Autor(en): Herrmann, Eric
Schäfer, Jan-Hannes
Wilmes, Stephan
Ungermann, Christian 
Moeller, Arne 
Kümmel, Daniel 
Stichwörter: Animals; Cryoelectron Microscopy; Endosomes; Guanine Nucleotide Exchange Factors; Protein Transport; rab GTP-Binding Proteins; Vesicular Transport Proteins; guanine nucleotide exchange factor; Rab protein; vesicular transport protein; animal; cryoelectron microscopy; endosome; metabolism; protein transport
Erscheinungsdatum: 2023
Herausgeber: National Academy of Sciences
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America
Band: 120
Ausgabe: 20
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. Copyright © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Cited by: 0; All Open Access, Green Open Access, Hybrid Gold Open Access
ISSN: 0027-8424
DOI: 10.1073/pnas.2301908120
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