MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes PMID: 38839979

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
13. Centre for Structural Systems Biology, Hamburg, Germany. [email protected].
14. European Molecular Biology Laboratory Hamburg, Hamburg, Germany. [email protected].
15. Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany. [email protected].
# Contributed equally.

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.