9kvx | pdb_00009kvx

Cryo-EM structure of SLC30A10 in Mn2+-bound state, determined in inward-facing conformation

Structural highlights

9kvx is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.79Å
Ligands:	MN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ZNT10_HUMAN Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

ZNT10_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 PubMed

Manganese 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

↑ Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, Del Rosario ML, Dyack S, Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012 Mar 9;90(3):457-66. PMID:22341972 doi:10.1016/j.ajhg.2012.01.018
↑ Patrushev N, Seidel-Rogol B, Salazar G. Angiotensin II requires zinc and downregulation of the zinc transporters ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells. PLoS One. 2012;7(3):e33211. PMID:22427991 doi:10.1371/journal.pone.0033211
↑ Leyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, Swaim CD, Morrisett RA, Bowman AB, Aschner M, Mukhopadhyay S. SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. J Neurosci. 2014 Oct 15;34(42):14079-95. PMID:25319704 doi:10.1523/JNEUROSCI.2329-14.2014
↑ Zhao Y, Feresin RG, Falcon-Perez JM, Salazar G. Differential Targeting of SLC30A10/ZnT10 Heterodimers to Endolysosomal Compartments Modulates EGF-Induced MEK/ERK1/2 Activity. Traffic. 2016 Mar;17(3):267-88. PMID:26728129 doi:10.1111/tra.12371
↑ Nishito Y, Tsuji N, Fujishiro H, Takeda TA, Yamazaki T, Teranishi F, Okazaki F, Matsunaga A, Tuschl K, Rao R, Kono S, Miyajima H, Narita H, Himeno S, Kambe T. Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter. J Biol Chem. 2016 Jul 8;291(28):14773-87. PMID:27226609 doi:10.1074/jbc.M116.728014
↑ Zogzas CE, Aschner M, Mukhopadhyay S. Structural Elements in the Transmembrane and Cytoplasmic Domains of the Metal Transporter SLC30A10 Are Required for Its Manganese Efflux Activity. J Biol Chem. 2016 Jul 29;291(31):15940-57. PMID:27307044 doi:10.1074/jbc.M116.726935
↑ Levy M, Elkoshi N, Barber-Zucker S, Hoch E, Zarivach R, Hershfinkel M, Sekler I. Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn(2+) is driven by an active Ca(2+)-coupled exchange. J Biol Chem. 2019 Apr 12;294(15):5879-5889. PMID:30755481 doi:10.1074/jbc.RA118.006816
↑ Shen X, Zhang JK, Sun P, Zhong H, He R, Wang S, Guo X, Yang H. Molecular mechanisms of SLC30A10-mediated manganese transport. Nat Commun. 2025 Sep 29;16(1):8581. PMID:41022720 doi:10.1038/s41467-025-63616-7

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OCA

[1] Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, Del Rosario ML, Dyack S, Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012 Mar 9;90(3):457-66. PMID:22341972 doi:10.1016/j.ajhg.2012.01.018

[2] Patrushev N, Seidel-Rogol B, Salazar G. Angiotensin II requires zinc and downregulation of the zinc transporters ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells. PLoS One. 2012;7(3):e33211. PMID:22427991 doi:10.1371/journal.pone.0033211

[3] Leyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, Swaim CD, Morrisett RA, Bowman AB, Aschner M, Mukhopadhyay S. SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. J Neurosci. 2014 Oct 15;34(42):14079-95. PMID:25319704 doi:10.1523/JNEUROSCI.2329-14.2014

[4] Zhao Y, Feresin RG, Falcon-Perez JM, Salazar G. Differential Targeting of SLC30A10/ZnT10 Heterodimers to Endolysosomal Compartments Modulates EGF-Induced MEK/ERK1/2 Activity. Traffic. 2016 Mar;17(3):267-88. PMID:26728129 doi:10.1111/tra.12371

[5] Nishito Y, Tsuji N, Fujishiro H, Takeda TA, Yamazaki T, Teranishi F, Okazaki F, Matsunaga A, Tuschl K, Rao R, Kono S, Miyajima H, Narita H, Himeno S, Kambe T. Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter. J Biol Chem. 2016 Jul 8;291(28):14773-87. PMID:27226609 doi:10.1074/jbc.M116.728014

[6] Zogzas CE, Aschner M, Mukhopadhyay S. Structural Elements in the Transmembrane and Cytoplasmic Domains of the Metal Transporter SLC30A10 Are Required for Its Manganese Efflux Activity. J Biol Chem. 2016 Jul 29;291(31):15940-57. PMID:27307044 doi:10.1074/jbc.M116.726935

[7] Levy M, Elkoshi N, Barber-Zucker S, Hoch E, Zarivach R, Hershfinkel M, Sekler I. Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn(2+) is driven by an active Ca(2+)-coupled exchange. J Biol Chem. 2019 Apr 12;294(15):5879-5889. PMID:30755481 doi:10.1074/jbc.RA118.006816

[8] Shen X, Zhang JK, Sun P, Zhong H, He R, Wang S, Guo X, Yang H. Molecular mechanisms of SLC30A10-mediated manganese transport. Nat Commun. 2025 Sep 29;16(1):8581. PMID:41022720 doi:10.1038/s41467-025-63616-7

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9kvx | pdb_00009kvx

Cryo-EM structure of SLC30A10 in Mn2+-bound state, determined in inward-facing conformation

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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