| Structural highlights
7n72 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[AT132_HUMAN] Autosomal recessive spastic paraplegia type 78;Kufor-Rakeb syndrome;ATP13A2-related juvenile neuronal ceroid lipofuscinosis. The disease is caused by variants affecting the gene represented in this entry. KRS has also been referred to as neuronal ceroid lipofuscinosis 12 (CLN12), due to neuronal and glial lipofuscin deposits detected in the cortex, basal nuclei and cerebellum of some patients.[1] The disease is caused by variants affecting the gene represented in this entry.
Function
[AT132_HUMAN] ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine (PubMed:31996848). Also stimulates cellular uptake of polyamines and protects against polyamine toxicity (PubMed:31996848). Plays a role in intracellular cation homeostasis and the maintenance of neuronal integrity (PubMed:22186024). Contributes to cellular zinc homeostasis (PubMed:24603074). Confers cellular protection against Mn(2+) and Zn(2+) toxicity and mitochondrial stress (PubMed:26134396). Required for proper lysosomal and mitochondrial maintenance (PubMed:22296644, PubMed:28137957). Regulates the autophagy-lysosome pathway through the control of SYT11 expression at both transcriptional and post-translational levels (PubMed:27278822). Facilitates recruitment of deacetylase HDAC6 to lysosomes to deacetylate CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy (PubMed:30538141). Promotes secretion of exosomes as well as secretion of SCNA via exosomes (PubMed:25392495, PubMed:24603074). Plays a role in lipid homeostasis (PubMed:31132336).[2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
Polyamines are small, organic polycations that are ubiquitous and essential to all forms of life. Currently, how polyamines are transported across membranes is not understood. Recent studies have suggested that ATP13A2 and its close homologs, collectively known as P5B-ATPases, are polyamine transporters at endo-/lysosomes. Loss-of-function mutations of ATP13A2 in humans cause hereditary early-onset Parkinson's disease. To understand the polyamine transport mechanism of ATP13A2, we determined high-resolution cryoelectron microscopy (cryo-EM) structures of human ATP13A2 in five distinct conformational intermediates, which together, represent a near-complete transport cycle of ATP13A2. The structural basis of the polyamine specificity was revealed by an endogenous polyamine molecule bound to a narrow, elongated cavity within the transmembrane domain. The structures show an atypical transport path for a water-soluble substrate, in which polyamines may exit within the cytosolic leaflet of the membrane. Our study provides important mechanistic insights into polyamine transport and a framework to understand the functions and mechanisms of P5B-ATPases.
Structural basis of polyamine transport by human ATP13A2 (PARK9).,Sim SI, von Bulow S, Hummer G, Park E Mol Cell. 2021 Oct 21. pii: S1097-2765(21)00684-5. doi:, 10.1016/j.molcel.2021.08.017. PMID:34715013[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bras J, Verloes A, Schneider SA, Mole SE, Guerreiro RJ. Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum Mol Genet. 2012 Jun 15;21(12):2646-50. doi: 10.1093/hmg/dds089. Epub 2012 Mar, 2. PMID:22388936 doi:http://dx.doi.org/10.1093/hmg/dds089
- ↑ Ramonet D, Podhajska A, Stafa K, Sonnay S, Trancikova A, Tsika E, Pletnikova O, Troncoso JC, Glauser L, Moore DJ. PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum Mol Genet. 2012 Apr 15;21(8):1725-43. doi: 10.1093/hmg/ddr606. Epub 2011 Dec , 20. PMID:22186024 doi:http://dx.doi.org/10.1093/hmg/ddr606
- ↑ Grunewald A, Arns B, Seibler P, Rakovic A, Munchau A, Ramirez A, Sue CM, Klein C. ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome. Neurobiol Aging. 2012 Aug;33(8):1843.e1-7. doi:, 10.1016/j.neurobiolaging.2011.12.035. Epub 2012 Jan 31. PMID:22296644 doi:http://dx.doi.org/10.1016/j.neurobiolaging.2011.12.035
- ↑ Kong SM, Chan BK, Park JS, Hill KJ, Aitken JB, Cottle L, Farghaian H, Cole AR, Lay PA, Sue CM, Cooper AA. Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-Synuclein externalization via exosomes. Hum Mol Genet. 2014 Jun 1;23(11):2816-33. doi: 10.1093/hmg/ddu099. Epub 2014 Mar , 6. PMID:24603074 doi:http://dx.doi.org/10.1093/hmg/ddu099
- ↑ Tsunemi T, Hamada K, Krainc D. ATP13A2/PARK9 regulates secretion of exosomes and alpha-synuclein. J Neurosci. 2014 Nov 12;34(46):15281-7. doi: 10.1523/JNEUROSCI.1629-14.2014. PMID:25392495 doi:http://dx.doi.org/10.1523/JNEUROSCI.1629-14.2014
- ↑ Holemans T, Sorensen DM, van Veen S, Martin S, Hermans D, Kemmer GC, Van den Haute C, Baekelandt V, Gunther Pomorski T, Agostinis P, Wuytack F, Palmgren M, Eggermont J, Vangheluwe P. A lipid switch unlocks Parkinson's disease-associated ATP13A2. Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):9040-5. doi:, 10.1073/pnas.1508220112. Epub 2015 Jul 1. PMID:26134396 doi:http://dx.doi.org/10.1073/pnas.1508220112
- ↑ Bento CF, Ashkenazi A, Jimenez-Sanchez M, Rubinsztein DC. The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat Commun. 2016 Jun 9;7:11803. doi: 10.1038/ncomms11803. PMID:27278822 doi:http://dx.doi.org/10.1038/ncomms11803
- ↑ Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(2):287-305. doi: 10.1093/brain/aww307. PMID:28137957 doi:http://dx.doi.org/10.1093/brain/aww307
- ↑ Wang R, Tan J, Chen T, Han H, Tian R, Tan Y, Wu Y, Cui J, Chen F, Li J, Lv L, Guan X, Shang S, Lu J, Zhang Z. ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome-lysosome fusion. J Cell Biol. 2019 Jan 7;218(1):267-284. doi: 10.1083/jcb.201804165. Epub 2018 Dec, 11. PMID:30538141 doi:http://dx.doi.org/10.1083/jcb.201804165
- ↑ Marcos AL, Corradi GR, Mazzitelli LR, Casali CI, Fernandez Tome MDC, Adamo HP, de Tezanos Pinto F. The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid homeostasis. Biochim Biophys Acta Biomembr. 2019 Oct 1;1861(10):182993. doi:, 10.1016/j.bbamem.2019.05.015. Epub 2019 May 24. PMID:31132336 doi:http://dx.doi.org/10.1016/j.bbamem.2019.05.015
- ↑ van Veen S, Martin S, Van den Haute C, Benoy V, Lyons J, Vanhoutte R, Kahler JP, Decuypere JP, Gelders G, Lambie E, Zielich J, Swinnen JV, Annaert W, Agostinis P, Ghesquiere B, Verhelst S, Baekelandt V, Eggermont J, Vangheluwe P. ATP13A2 deficiency disrupts lysosomal polyamine export. Nature. 2020 Feb;578(7795):419-424. doi: 10.1038/s41586-020-1968-7. Epub 2020 Jan, 29. PMID:31996848 doi:http://dx.doi.org/10.1038/s41586-020-1968-7
- ↑ Sim SI, von Bulow S, Hummer G, Park E. Structural basis of polyamine transport by human ATP13A2 (PARK9). Mol Cell. 2021 Oct 21. pii: S1097-2765(21)00684-5. doi:, 10.1016/j.molcel.2021.08.017. PMID:34715013 doi:http://dx.doi.org/10.1016/j.molcel.2021.08.017
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