BORC assemblies integrate BLOC-1 subunits to diversify endosomal trafficking functions
Abstract
BORC and BLOC-1 are multisubunit complexes that regulate endolysosomal trafficking. Although they are presumed to be distinct, their paralogous origins and shared subunits suggest the potential for higher-order assembly. Here, we reveal the conserved octameric architecture of BORC formed by two intertwined tetramers and present the structure of C. elegans BORC. Through cross-linking mass spectrometry of endogenous complexes, we validate this model for human BORC and demonstrate that the integrity of the complex, which is essential for lysosomal transport, relies on specific interfacial residues. We also clarify the disruptive nature of disease-causing mutations and propose that the formation and function of BORC are likely regulated by specific cues. These cues might include the phosphorylation of Snapin and a pH-sensitive histidine residue in BORCS5. Additionally, we present direct biochemical and structural evidence of BORC–BLOC-1 hybrid complexes. Finally, we link a specific hybrid complex to the regulation of transferrin receptor recycling via interaction with the EARP complex. Our work challenges the paradigm of BORC and BLOC-1 as separate entities, establishing a model of dynamic complex formation wherein modular assembly creates functional specialization to meet diverse cellular demands.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Mariana E. G. de Araujo
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Sascha J. Amann
Research Institute of Molecular Pathology, Vienna BioCenter
Taras Stasyk
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Alexander Schleiffer
Eva Rauch
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Paula Flümann
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Isabel I. Singer
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Leopold Kremser
Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck
Vojtech Dostal
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Thanida Laopanupong
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Nikolaus Obojes
Institute for Alpine Environment, Eurac Research
Moritz H. Wallnöfer
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Flora S. Gradl
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Robert Kurzbauer
Research Institute of Molecular Pathology, Vienna BioCenter
Caroline Krebiehl
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Samuel Kofler
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Irina Grishkovskaya
Research Institute of Molecular Pathology, Vienna BioCenter
Georg F. Vogel
Institute of Cell Biology, Biocenter, Medical University of Innsbruck
Michael W. Hess
Institute of Histology and Embryology, Medical University of Innsbruck
Bettina Sarg
Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck
Tim Clausen
David Haselbach
Research Institute of Molecular Pathology, Vienna BioCenter
Lukas A. Huber
Institute of Cell Biology, Biocenter, Medical University of Innsbruck