9kvx
From Proteopedia
Cryo-EM structure of SLC30A10 in Mn2+-bound state, determined in inward-facing conformation
Structural highlights
DiseaseZNT10_HUMAN Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionZNT10_HUMAN Calcium:manganese antiporter of the plasma membrane mediating the efflux of intracellular manganese coupled to an active extracellular calcium exchange (PubMed:30755481). Required for intracellular manganese homeostasis, an essential cation for the function of several enzymes, including some crucially important for the metabolism of neurotransmitters and other neuronal metabolic pathways. Manganese can also be cytotoxic and induce oxidative stress, mitochondrial dysfunction and apoptosis (PubMed:22341972, PubMed:25319704, PubMed:26728129, PubMed:27226609, PubMed:27307044). Could also have an intracellular zinc ion transporter activity, directly regulating intracellular zinc ion homeostasis and more indirectly various signaling pathway and biological processes (PubMed:22427991, PubMed:26728129).[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedManganese ion (Mn(2)(+)) is crucial for various physiological processes, yet excessive levels disrupt cellular homeostasis and impair the function of multiple organelles. The transporter SLC30A10 plays a pivotal role in Mn(2)(+) homeostasis by exporting Mn(2)(+) from cells, preventing toxic effects. Mutations in the SLC30A10 gene result in Mn(2)(+) accumulation and lead to disorders such as hypermanganesemia with dystonia 1 (HMNDYT1). Despite its physiological significance, the structural basis underlying Mn(2)(+) binding and the detailed transport mechanisms of SLC30A10 remain unknown. Here, we present diverse conformations of high-resolution cryo-electron microscopy (cryo-EM) structures that reveal a Mn(2)(+)-binding site in SLC30A10, setting it apart from other SLC30 family transporters. Furthermore, we show that the HMNDYT1-associated D40A mutation interrupts Mn(2)(+) binding and transport, identifying D40 as a potential therapeutic target. These findings provide structural insights into Mn(2)(+) transport mechanisms mediated by SLC30A10, advancing our understanding of Mn(2)(+) binding and potential targets for future therapeutic exploration. Molecular mechanisms of SLC30A10-mediated manganese transport.,Shen X, Zhang JK, Sun P, Zhong H, He R, Wang S, Guo X, Yang H Nat Commun. 2025 Sep 29;16(1):8581. doi: 10.1038/s41467-025-63616-7. PMID:41022720[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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