2. Academic Validation
  3. MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes

MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes

  • Nat Cell Biol. 2024 Jun 5. doi: 10.1038/s41556-024-01436-5.
Katharina Esther Julia Jungnickel # 1 2,  Océane Guelle # 3,  Miharu Iguchi 4 5 6,  Wentao Dong 4 5 6,  Vadim Kotov 1 2,  Florian Gabriel 1 2,  Cécile Debacker 3,  Julien Dairou 7,  Isabelle McCort-Tranchepain 7,  Nouf N Laqtom 4 5 6,  Sze Ham Chan 8,  Akika Ejima 9,  Kenji Sato 9,  David Massa López 10,  Paul Saftig 10,  Ahmad Reza Mehdipour 11,  Monther Abu-Remaileh 4 5 6,  Bruno Gasnier 12,  Christian Löw 13 14,  Markus Damme 15
Affiliations

Affiliations

  • 1 Centre for Structural Systems Biology, Hamburg, Germany.
  • 2 European Molecular Biology Laboratory Hamburg, Hamburg, Germany.
  • 3 Saints-Pères Paris Institute for the Neurosciences, Université Paris Cité, Centre National de la Recherche Scientifique, Paris, France.
  • 4 Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
  • 5 Department of Genetics, Stanford University, Stanford, CA, USA.
  • 6 The Institute for Chemistry, Engineering and Medicine for Human Health, Stanford University, Stanford, CA, USA.
  • 7 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Université Paris Cité, Paris, France.
  • 8 Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 9 Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
  • 10 Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
  • 11 UGent Center for Molecular Modeling, Ghent University, Ghent, Belgium.
  • 12 Saints-Pères Paris Institute for the Neurosciences, Université Paris Cité, Centre National de la Recherche Scientifique, Paris, France. bruno.gasnier@u-paris.fr.
  • 13 Centre for Structural Systems Biology, Hamburg, Germany. christian.loew@embl-hamburg.de.
  • 14 European Molecular Biology Laboratory Hamburg, Hamburg, Germany. christian.loew@embl-hamburg.de.
  • 15 Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany. mdamme@biochem.uni-kiel.de.
  • # Contributed equally.
PMID: 38839979 DOI: 10.1038/s41556-024-01436-5
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.

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