MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes
Year: 2024
Type: article
Abstract: The lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator superfamily domain containing 1 (MFSD1) protein, which forms a tight complex with the glycosylated lysosomal membrane protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer and fluorescence-based studies in Xenopus oocytes and proteoliposomes showed that MFSD1-GLMP acts as a uniporter for cationic, neutral and anionic dipeptides. Cryoelectron microscopy structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded.
Source: Nature Cell Biology
Authors: Katharina Esther Julia Jungnickel, Océane Guelle, Miharu Iguchi, Wentao Dong, Vadim Kotov, Florian Gabriel, Cécile Debacker, Julien Dairou, Isabelle McCort-Tranchepain, Nouf N. Laqtom, Sze Ham Chan, Akika Ejima, Kenji Sato, David Massa López, Paul Saftig, Ahmad Reza Mehdipour, Monther Abu-Remaileh, Bruno Gasnier, Christian Löw, Markus Damme
Institutions: European Molecular Biology Laboratory, Centre for Structural Systems Biology, Centre National de la Recherche Scientifique, Université Paris Cité, SPPIN - Saints-Pères Paris Institute for Neurosciences, Stanford University, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, University of Virginia, Kyoto University, Christian-Albrechts-Universität zu Kiel, Ghent University
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Funders: Alexander and Margaret Stewart Trust, European Molecular Biology Laboratory, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Bundesministerium für Bildung und Forschung, Christian-Albrechts-Universität zu Kiel, Centre National de la Recherche Scientifique, Université de Paris
Awards: G1207555334, G126185643, G141864249, G1726472266, Dynamics of lysosomal amino acid transporters, G2795764212, G2833411440, G2878621099, G3064899179, G3785499967, G3836831239, G43492377, G4462369699, G4656594441, G521208723, G610835798, G615087449, G6214718417, G6658462857, G7044854202, G7186456264, G7210000211, G7673705747, Mechanism of lysosomal signaling by an amino acid transceptor
OpenAlex ID: W4399360680