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XB-ART-60723
Nat Cell Biol 2024 Jun 05; doi: 10.1038/s41556-024-01436-5.
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MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes.

Jungnickel KEJ , Guelle O , Iguchi M , Dong W , Kotov V , Gabriel F , Debacker C , Dairou J , McCort-Tranchepain I , Laqtom NN , Chan SH , Ejima A , Sato K , Massa López D , Saftig P , Mehdipour AR , Abu-Remaileh M , Gasnier B , Löw C , Damme M .


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.

PubMed ID: 38839979
Article link: Nat Cell Biol
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