Year: 2026
Type: article
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.
Authors: Mariana E. G. de Araujo, Sascha J. Amann, Taras Stasyk, Alexander Schleiffer, Eva Rauch, Paula Flümann, Isabel I. Singer, Leopold Kremser, Vojtech Dostal, Thanida Laopanupong, Nikolaus Obojes, Moritz H. Wallnöfer, Flora S. Gradl, Robert Kurzbauer, Caroline Krebiehl, Samuel Kofler, Irina Grishkovskaya, Georg F. Vogel, Michael W. Hess, Bettina Sarg, Tim Clausen, David Haselbach, Lukas A. Huber
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: Imaging of DNA folding by cohesin through time resolved single molecule light, atomic force and cryo-electron microscopy, Cellular Basis of Diseases: Molecular Control of Metabolism and Inflammation, Structure-function analyses of the BORC, G5072808781, Molecular architecture of native LAMTOR and BORC assemblies, G645210558, G8170311165, G8590477180
OpenAlex ID: W7124970920