Molecular mechanisms of SLC30A10-mediated manganese transport

Xurui Shen, Jinlun Kylian Zhang, Peixin Sun, Huiwen Zhong, Rui He, Shiliang Wang, Xiaojun Guo and Hanting Yang ()
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Xurui Shen: Fudan University
Jinlun Kylian Zhang: Fudan University
Peixin Sun: Fudan University
Huiwen Zhong: Fudan University
Rui He: Fudan University
Shiliang Wang: Fudan University
Xiaojun Guo: Fudan University
Hanting Yang: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Manganese ion (Mn²⁺) 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 Mn²⁺ homeostasis by exporting Mn²⁺ from cells, preventing toxic effects. Mutations in the SLC30A10 gene result in Mn²⁺ accumulation and lead to disorders such as hypermanganesemia with dystonia 1 (HMNDYT1). Despite its physiological significance, the structural basis underlying Mn²⁺ 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 Mn²⁺-binding site in SLC30A10, setting it apart from other SLC30 family transporters. Furthermore, we show that the HMNDYT1-associated D40A mutation interrupts Mn²⁺ binding and transport, identifying D40 as a potential therapeutic target. These findings provide structural insights into Mn²⁺ transport mechanisms mediated by SLC30A10, advancing our understanding of Mn²⁺ binding and potential targets for future therapeutic exploration.

Date: 2025
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DOI: 10.1038/s41467-025-63616-7

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