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MFSD1 与其辅助亚基 GLMP 一起作为溶酶体中的通用二肽转运蛋白发挥作用。

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

机构信息

Centre for Structural Systems Biology, Hamburg, Germany.

European Molecular Biology Laboratory Hamburg, Hamburg, Germany.

出版信息

Nat Cell Biol. 2024 Jul;26(7):1047-1061. doi: 10.1038/s41556-024-01436-5. Epub 2024 Jun 5.

DOI:10.1038/s41556-024-01436-5
PMID:38839979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11252000/
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.

摘要

溶酶体对大分子的降解产生了各种不同的小代谢物，这些代谢物通过特定的转运蛋白输出，用于生物合成途径中的再利用。在这里，我们对主要易位子超家族结构域包含蛋白 1（MFSD1）进行了基因功能鉴定，该蛋白在溶酶体膜上与糖基化溶酶体膜蛋白（GLMP）形成紧密复合物。对 MFSD1 缺陷型小鼠溶酶体的非靶向代谢组学分析显示，阳离子二肽增加。纯化的 MFSD1 选择性结合多种二肽，而在非洲爪蟾卵母细胞和质体蓝素体中的电生理学、同位素示踪和荧光研究表明，MFSD1-GLMP 作为阳离子、中性和阴离子二肽的协同转运蛋白发挥作用。结合分子动力学模拟，二肽结合 MFSD1-GLMP 复合物的向外开放构象的冷冻电镜结构确定了异二聚体界面，并为其对各种二肽的选择性提供了结构基础。总之，我们的数据将 MFSD1 鉴定为一种通用的溶酶体二肽协同转运蛋白，当溶酶体氨基酸外排系统过载时，它提供了一种回收溶酶体蛋白水解产物的替代途径。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf77/11252000/caa7600d92d5/41556_2024_1436_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf77/11252000/d278fb567848/41556_2024_1436_Fig14_ESM.jpg
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Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology.溶酶体作为细胞分解代谢、代谢信号和器官生理学的协调者。
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Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1.
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