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3.A.3.10.7
This protein, ATP13A2, 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 probable 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).

Accession Number:Q9NQ11
Protein Name:Probable cation-transporting ATPase 13A2 aka FUPA13a
Length:1180
Molecular Weight:128794.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:11
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate

Cross database links:

RefSeq: NP_001135446.1    NP_071372.1   
Entrez Gene ID: 23400   
Pfam: PF00122    PF00702   
OMIM: 606693  phenotype
610513  gene

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005524 F:ATP binding
GO:0015662 F:ATPase activity, coupled to transmembrane m...
GO:0046872 F:metal ion binding
GO:0006754 P:ATP biosynthetic process
GO:0006812 P:cation transport

References (7)

[1] “The DNA sequence and biological annotation of human chromosome 1.”  Gregory S.G.et.al.   16710414
[2] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[3] “The full-ORF clone resource of the German cDNA consortium.”  Bechtel S.et.al.   17974005
[4] “Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.”  Ramirez A.et.al.   16964263
[5] “ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.”  Di Fonzo A.et.al.   17485642
[6] “Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore.”  Lin C.H.et.al.   19015489
[7] “ATP13A2 variability in Parkinson disease.”  Vilarino-Guell C.et.al.   19085912

External Searches:

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MSADSSPLVG STPTGYGTLT IGTSIDPLSS SVSSVRLSGY CGSPWRVIGY HVVVWMMAGI 
61:	PLLLFRWKPL WGVRLRLRPC NLAHAETLVI EIRDKEDSSW QLFTVQVQTE AIGEGSLEPS 
121:	PQSQAEDGRS QAAVGAVPEG AWKDTAQLHK SEEAVSVGQK RVLRYYLFQG QRYIWIETQQ 
181:	AFYQVSLLDH GRSCDDVHRS RHGLSLQDQM VRKAIYGPNV ISIPVKSYPQ LLVDEALNPY 
241:	YGFQAFSIAL WLADHYYWYA LCIFLISSIS ICLSLYKTRK QSQTLRDMVK LSMRVCVCRP 
301:	GGEEEWVDSS ELVPGDCLVL PQEGGLMPCD AALVAGECMV NESSLTGESI PVLKTALPEG 
361:	LGPYCAETHR RHTLFCGTLI LQARAYVGPH VLAVVTRTGF CTAKGGLVSS ILHPRPINFK 
421:	FYKHSMKFVA ALSVLALLGT IYSIFILYRN RVPLNEIVIR ALDLVTVVVP PALPAAMTVC 
481:	TLYAQSRLRR QGIFCIHPLR INLGGKLQLV CFDKTGTLTE DGLDVMGVVP LKGQAFLPLV 
541:	PEPRRLPVGP LLRALATCHA LSRLQDTPVG DPMDLKMVES TGWVLEEEPA ADSAFGTQVL 
601:	AVMRPPLWEP QLQAMEEPPV PVSVLHRFPF SSALQRMSVV VAWPGATQPE AYVKGSPELV 
661:	AGLCNPETVP TDFAQMLQSY TAAGYRVVAL ASKPLPTVPS LEAAQQLTRD TVEGDLSLLG 
721:	LLVMRNLLKP QTTPVIQALR RTRIRAVMVT GDNLQTAVTV ARGCGMVAPQ EHLIIVHATH 
781:	PERGQPASLE FLPMESPTAV NGVKDPDQAA SYTVEPDPRS RHLALSGPTF GIIVKHFPKL 
841:	LPKVLVQGTV FARMAPEQKT ELVCELQKLQ YCVGMCGDGA NDCGALKAAD VGISLSQAEA 
901:	SVVSPFTSSM ASIECVPMVI REGRCSLDTS FSVFKYMALY SLTQFISVLI LYTINTNLGD 
961:	LQFLAIDLVI TTTVAVLMSR TGPALVLGRV RPPGALLSVP VLSSLLLQMV LVTGVQLGGY 
1021:	FLTLAQPWFV PLNRTVAAPD NLPNYENTVV FSLSSFQYLI LAAAVSKGAP FRRPLYTNVP 
1081:	FLVALALLSS VLVGLVLVPG LLQGPLALRN ITDTGFKLLL LGLVTLNFVG AFMLESVLDQ 
1141:	CLPACLRRLR PKRASKKRFK QLERELAEQP WPPLPAGPLR