3.A.3.10.7
This protein, ATP13A2 or P5A ATPase or ATP13A(1), was orginally designated the functionally uncharacterized P-type ATPase, FUPA13 (Thever and Saier 2009).  It is the Parkinson''s disease (PD) gene product, PARK9 (ATP13A2), and its defect gives rise to multiple abnormalities (Dehay et al. 2012).  It is similar to the incorrectly assigned manganese exporter in yeast, Ypk1 (TC# 3.A.3.10.8), and may have the same function, but in lysosomes, it is a polyamine (spermine/spermidine) exporter (van Veen et al. 2020). Toxic levels of manganese or abnormal levels of polyamines may cause a syndrome simiilar to PD (Chesi et al. 2012).  Manganese homeostasis in the nervous system has been reviewed (Chen et al. 2015).  The progression of PD may involve the lysosome and different autophagy pathways (Gan-Or et al. 2015).  It exhibits an activity-independent scaffolding role in trafficking/export of intracellular cargo in response to proteotoxic stress (Demirsoy et al. 2017). Mutations cause rare early onset Parkinson's disease (Suleiman et al. 2018). ATP13A2 modulates astrocyte-mediated neuroinflammation via NLRP3 inflammasome activation, thus bringing to light a direct link between astrocyte lysosomes and neuroinflammation in the pathological model of PD (Qiao et al. 2016). ATP13A2 and its close homologs, collectively known as P5B-ATPases, are polyamine transporters in endo-/lysosomes. Cryo-EM structures of human ATP13A2 in five distinct conformational intermediates, which together, represent a near-complete transport cycle of ATP13A2, have been determined. 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 (Sim et al. 2021). Spermine is exported from the lysosome. The transmembrane domain serves as a substrate binding site, and the C-terminal domain is essential for protein stability and may play a regulatory role (Chen et al. 2021). The carcinogenic effects of ATP13A2 in different tumors has been studied (Zheng and Li 2021). High-resolution cryo-EM structures of human ATP13A2 in five distinct conformational intermediates have been determined, 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 (Sim et al. 2021). Mutations in ATP13A2 aare associated with mixed neurological presentations and iron toxicity due to nonsense-mediated decay (Kırımtay et al. 2021). The importance of the protein in regulating neuronal integrity has been established, and the structural dynamics and catalytic mechanism have been proposed (Mateeva et al. 2021). It is an ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine, and also stimulates cellular uptake of polyamines and protects against polyamine toxicity (van Veen et al. 2020; Sim and Park 2023). Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2 is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78. It is a transporter that balances the polyamine concentration between the lysosome and the cytosol. Single-particle cryo-EM solved high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway (Mu et al. 2023).