Cross-linking of the endolysosomal system reveals potential flotillin structures and cargo

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Singh, Jasjot ; Elhabashy, Hadeer ; Muthukottiappan, Pathma ; Stepath, Markus ; Eisenacher, Martin ; Kohlbacher, Oliver ; Gieselmann, Volkmar ; Winter, Dominic:
Cross-linking of the endolysosomal system reveals potential flotillin structures and cargo.
In: Nature Communications. Bd. 13 (2022) . - 6212.
ISSN 2041-1723
DOI: https://doi.org/10.1038/s41467-022-33951-0

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Abstract

Lysosomes are well-established as the main cellular organelles for the degradation of macromolecules and emerging as regulatory centers of metabolism. They are of crucial importance for cellular homeostasis, which is exemplified by a plethora of disorders related to alterations in lysosomal function. In this context, protein complexes play a decisive role, regulating not only metabolic lysosomal processes but also lysosome biogenesis, transport, and interaction with other organelles. Using cross-linking mass spectrometry, we analyze lysosomes and early endosomes. Based on the identification of 5376 cross-links, we investigate protein-protein interactions and structures of lysosome- and endosome-related proteins. In particular, we present evidence for a tetrameric assembly of the lysosomal hydrolase PPT1 and a heterodimeric structure of FLOT1/FLOT2 at lysosomes and early endosomes. For FLOT1-/FLOT2-positive early endosomes, we identify >300 putative cargo proteins and confirm eleven substrates for flotillin-dependent endocytosis, including the latrophilin family of adhesion G protein-coupled receptors.