ID AT1A2_HUMAN Reviewed; 1020 AA. AC P50993; D3DVE4; Q07059; Q5JW74; Q86UZ5; Q9UQ25; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 27-MAR-2024, entry version 222. DE RecName: Full=Sodium/potassium-transporting ATPase subunit alpha-2; DE Short=Na(+)/K(+) ATPase alpha-2 subunit; DE EC=7.2.2.13; DE AltName: Full=Sodium pump subunit alpha-2; DE Flags: Precursor; GN Name=ATP1A2; Synonyms=KIAA0778; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2477373; DOI=10.1016/s0021-9258(18)71525-1; RA Shull M.M., Pugh D.G., Lingrel J.B.; RT "Characterization of the human Na,K-ATPase alpha 2 gene and identification RT of intragenic restriction fragment length polymorphisms."; RL J. Biol. Chem. 264:17532-17543(1989). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=9872452; DOI=10.1093/dnares/5.5.277; RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Miyajima N., Tanaka A., RA Kotani H., Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XI. The RT complete sequences of 100 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 5:277-286(1998). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 211-249. RC TISSUE=Leukocyte; RX PubMed=3035563; DOI=10.1073/pnas.84.12.4039; RA Shull M.M., Lingrel J.B.; RT "Multiple genes encode the human Na+,K+-ATPase catalytic subunit."; RL Proc. Natl. Acad. Sci. U.S.A. 84:4039-4043(1987). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 251-442. RC TISSUE=Brain, and Placenta; RX PubMed=3036582; DOI=10.1016/0014-5793(87)80677-4; RA Sverdlov E.D., Monastyrskaya G.S., Broude N.E., Ushkaryov Y.A., RA Allikmets R.L., Melkov A.M., Smirnov Y.V., Malyshev I.V., Dulubova I.E., RA Petrukhin K.E., Gryshin A.V., Kiyatkin N.I., Kostina M.B., Sverdlov V.E., RA Modyanov N.N., Ovchinnikov Y.A.; RT "The family of human Na+,K+-ATPase genes. No less than five genes and/or RT pseudogenes related to the alpha-subunit."; RL FEBS Lett. 217:275-278(1987). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-4. RX PubMed=2537767; DOI=10.1016/0014-5793(89)80588-5; RA Sverdlov E.D., Bessarab D.A., Malyshev I.V., Petrukhin K.E., Smirnov Y.V., RA Ushkaryov Y.A., Monastyrskaya G.S., Broude N.E., Modyanov N.N.; RT "Family of human Na+,K+-ATPase genes. Structure of the putative regulatory RT region of the alpha+-gene."; RL FEBS Lett. 244:481-483(1989). RN [9] RP SUBCELLULAR LOCATION. RX PubMed=7711835; DOI=10.3109/09687689409160435; RA Hundal H.S., Maxwell D.L., Ahmed A., Darakhshan F., Mitsumoto Y., Klip A.; RT "Subcellular distribution and immunocytochemical localization of Na,K- RT ATPase subunit isoforms in human skeletal muscle."; RL Mol. Membr. Biol. 11:255-262(1994). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-570 AND SER-587, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [11] RP VARIANTS FHM2 GLN-689 AND THR-731. RX PubMed=12953268; DOI=10.1002/ana.10674; RA Vanmolkot K.R.J., Kors E.E., Hottenga J.-J., Terwindt G.M., Haan J., RA Hoefnagels W.A.J., Black D.F., Sandkuijl L.A., Frants R.R., Ferrari M.D., RA van den Maagdenberg A.M.J.M.; RT "Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with RT familial hemiplegic migraine and benign familial infantile convulsions."; RL Ann. Neurol. 54:360-366(2003). RN [12] RP VARIANTS FHM2 PRO-764 AND ARG-887, AND CHARACTERIZATION OF VARIANTS FMH2 RP PRO-764 AND ARG-887. RX PubMed=12539047; DOI=10.1038/ng1081; RA De Fusco M., Marconi R., Silvestri L., Atorino L., Rampoldi L., RA Morgante L., Ballabio A., Aridon P., Casari G.; RT "Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit RT associated with familial hemiplegic migraine type 2."; RL Nat. Genet. 33:192-196(2003). RN [13] RP VARIANT AHC1 ASN-378. RX PubMed=15174025; DOI=10.1002/ana.20134; RA Swoboda K.J., Kanavakis E., Xaidara A., Johnson J.E., Leppert M.F., RA Schlesinger-Massart M.B., Ptacek L.J., Silver K., Youroukos S.; RT "Alternating hemiplegia of childhood or familial hemiplegic migraine? A RT novel ATP1A2 mutation."; RL Ann. Neurol. 55:884-887(2004). RN [14] RP VARIANT FHM2 ARG-715. RX PubMed=21352219; DOI=10.1111/j.1526-4610.2010.01793.x; RA De Sanctis S., Grieco G.S., Breda L., Casali C., Nozzi M., Del Torto M., RA Chiarelli F., Verrotti A.; RT "Prolonged sporadic hemiplegic migraine associated with a novel de novo RT missense ATP1A2 gene mutation."; RL Headache 51:447-450(2011). RN [15] RP VARIANT FHM2 TRP-1007. RX PubMed=23838748; DOI=10.1177/0333102413495116; RA Pisano T., Spiller S., Mei D., Guerrini R., Cianchetti C., Friedrich T., RA Pruna D.; RT "Functional characterization of a novel C-terminal ATP1A2 mutation causing RT hemiplegic migraine and epilepsy."; RL Cephalalgia 33:1302-1310(2013). RN [16] RP VARIANT FHM2 SER-874. RX PubMed=23918834; DOI=10.1177/0333102413498941; RA Costa C., Prontera P., Sarchielli P., Tonelli A., Bassi M.T., Cupini L.M., RA Caproni S., Siliquini S., Donti E., Calabresi P.; RT "A novel ATP1A2 gene mutation in familial hemiplegic migraine and RT epilepsy."; RL Cephalalgia 34:68-72(2014). RN [17] RP VARIANTS DEE98 ALA-366 AND TRP-593. RX PubMed=27864847; DOI=10.1002/humu.23149; RG Clinical Study Group; RA Parrini E., Marini C., Mei D., Galuppi A., Cellini E., Pucatti D., RA Chiti L., Rutigliano D., Bianchini C., Virdo S., De Vita D., Bigoni S., RA Barba C., Mari F., Montomoli M., Pisano T., Rosati A., Guerrini R.; RT "Diagnostic targeted resequencing in 349 patients with drug-resistant RT pediatric epilepsies identifies causative mutations in 30 different RT genes."; RL Hum. Mutat. 38:216-225(2017). RN [18] RP VARIANT FARIMPD 957-GLU--TYR-1020 DEL, AND INVOLVEMENT IN FARIMPD. RX PubMed=31608932; DOI=10.1093/brain/awz272; RA Chatron N., Cabet S., Alix E., Buenerd A., Cox P., Guibaud L., Labalme A., RA Marks P., Osio D., Putoux A., Sanlaville D., Lesca G., Vasiljevic A.; RT "A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 RT homozygous truncating variants."; RL Brain 142:3367-3374(2019). RN [19] RP INVOLVEMENT IN FARIMPD. RX PubMed=30690204; DOI=10.1016/j.ejmg.2019.01.014; RA Monteiro F.P., Curry C.J., Hevner R., Elliott S., Fisher J.H., Turocy J., RA Dobyns W.B., Costa L.A., Freitas E., Kitajima J.P., Kok F.; RT "Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, RT microcephaly, arthrogryposis and extensive cortical malformations."; RL Eur. J. Med. Genet. 63:103624-103624(2020). RN [20] RP VARIANTS DEE98 MET-293; PHE-341; ALA-366 AND GLN-908, INVOLVEMENT IN DEE98, RP FUNCTION, CHARACTERIZATION OF VARIANTS DEE98 MET-293; ALA-366 AND GLN-908, RP VARIANT GLN-593, AND CHARACTERIZATION OF VARIANT GLN-593. RX PubMed=33880529; DOI=10.1093/brain/awab052; RG ATP1A2/A3-collaborators; RA Vetro A., Nielsen H.N., Holm R., Hevner R.F., Parrini E., Powis Z., RA Moeller R.S., Bellan C., Simonati A., Lesca G., Helbig K.L., Palmer E.E., RA Mei D., Ballardini E., Van Haeringen A., Syrbe S., Leuzzi V., Cioni G., RA Curry C.J., Costain G., Santucci M., Chong K., Mancini G.M.S., RA Clayton-Smith J., Bigoni S., Scheffer I.E., Dobyns W.B., Vilsen B., RA Guerrini R.; RT "ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and RT polymicrogyria."; RL Brain 144:1435-1450(2021). CC -!- FUNCTION: This is the catalytic component of the active enzyme, which CC catalyzes the hydrolysis of ATP coupled with the exchange of sodium and CC potassium ions across the plasma membrane. This action creates the CC electrochemical gradient of sodium and potassium, providing the energy CC for active transport of various nutrients. CC {ECO:0000269|PubMed:33880529}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O + K(+)(out) + Na(+)(in) = ADP + H(+) + K(+)(in) + CC Na(+)(out) + phosphate; Xref=Rhea:RHEA:18353, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29101, ChEBI:CHEBI:29103, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; CC EC=7.2.2.13; CC -!- SUBUNIT: The sodium/potassium-transporting ATPase is composed of a CC catalytic alpha subunit, an auxiliary non-catalytic beta subunit and an CC additional regulatory subunit. Interacts with regulatory subunit FXYD1. CC {ECO:0000250|UniProtKB:A2VDL6}. CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:7711835}; Multi-pass CC membrane protein {ECO:0000269|PubMed:7711835}. Cell membrane CC {ECO:0000269|PubMed:7711835}; Multi-pass membrane protein CC {ECO:0000269|PubMed:7711835}. CC -!- DISEASE: Migraine, familial hemiplegic, 2 (FHM2) [MIM:602481]: A CC subtype of migraine with aura associated with hemiparesis in some CC families. Migraine is a disabling symptom complex of periodic CC headaches, usually temporal and unilateral. Headaches are often CC accompanied by irritability, nausea, vomiting and photophobia, preceded CC by constriction of the cranial arteries. Migraine with aura is CC characterized by recurrent attacks of reversible neurological symptoms CC (aura) that precede or accompany the headache. Aura may include a CC combination of sensory disturbances, such as blurred vision, CC hallucinations, vertigo, numbness and difficulty in concentrating and CC speaking. {ECO:0000269|PubMed:12539047, ECO:0000269|PubMed:12953268, CC ECO:0000269|PubMed:21352219, ECO:0000269|PubMed:23838748, CC ECO:0000269|PubMed:23918834}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Alternating hemiplegia of childhood 1 (AHC1) [MIM:104290]: A CC rare syndrome of episodic hemi- or quadriplegia lasting minutes to CC days. Most cases are accompanied by dystonic posturing, choreoathetoid CC movements, nystagmus, other ocular motor abnormalities, autonomic CC disturbances, and progressive cognitive impairment. It is typically CC distinguished from familial hemiplegic migraine by infantile onset and CC high prevalence of associated neurological deficits that become CC increasingly obvious with age. {ECO:0000269|PubMed:15174025}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Fetal akinesia, respiratory insufficiency, microcephaly, CC polymicrogyria, and dysmorphic facies (FARIMPD) [MIM:619602]: An CC autosomal recessive disease characterized by fetal akinesia, and CC generalized joint contractures and arthrogryposis at birth. Affected CC newborns have severe respiratory insufficiency and significant CC dysmorphic facial features. Malformations of cortical development are CC seen on brain imaging, most commonly polymicrogyria or other gyral CC anomalies. Death usually occurs in infancy. CC {ECO:0000269|PubMed:30690204, ECO:0000269|PubMed:31608932}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Developmental and epileptic encephalopathy 98 (DEE98) CC [MIM:619605]: A form of epileptic encephalopathy, a heterogeneous group CC of early-onset epilepsies characterized by refractory seizures, CC neurodevelopmental impairment, and poor prognosis. Development is CC normal prior to seizure onset, after which cognitive and motor delays CC become apparent. DEE98 is an autosomal dominant form characterized by CC onset of seizures in the first decade. {ECO:0000269|PubMed:27864847, CC ECO:0000269|PubMed:33880529}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type) (TC 3.A.3) CC family. Type IIC subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA34498.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J05096; AAA51797.1; -; Genomic_DNA. DR EMBL; AB018321; BAA34498.2; ALT_INIT; mRNA. DR EMBL; AL121987; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471121; EAW52740.1; -; Genomic_DNA. DR EMBL; CH471121; EAW52741.1; -; Genomic_DNA. DR EMBL; BC052271; AAH52271.2; -; mRNA. DR EMBL; M16795; AAA51799.1; -; mRNA. DR EMBL; M27578; AAA35575.1; -; Genomic_DNA. DR EMBL; M27571; AAA35575.1; JOINED; Genomic_DNA. DR EMBL; M27576; AAA35575.1; JOINED; Genomic_DNA. DR EMBL; Y07494; CAA68793.1; ALT_SEQ; mRNA. DR CCDS; CCDS1196.1; -. DR PIR; A34474; A34474. DR RefSeq; NP_000693.1; NM_000702.3. DR AlphaFoldDB; P50993; -. DR SMR; P50993; -. DR BioGRID; 106967; 45. DR IntAct; P50993; 21. DR MINT; P50993; -. DR STRING; 9606.ENSP00000354490; -. DR BindingDB; P50993; -. DR ChEMBL; CHEMBL2095186; -. DR DrugBank; DB09020; Bisacodyl. DR DrugBank; DB01092; Ouabain. DR DrugBank; DB09479; Rubidium Rb-82. DR DrugBank; DB16690; Tegoprazan. DR DrugCentral; P50993; -. DR TCDB; 3.A.3.1.1; the p-type atpase (p-atpase) superfamily. DR GlyCosmos; P50993; 1 site, 1 glycan. DR GlyGen; P50993; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P50993; -. DR PhosphoSitePlus; P50993; -. DR SwissPalm; P50993; -. DR BioMuta; ATP1A2; -. DR DMDM; 1703467; -. DR EPD; P50993; -. DR jPOST; P50993; -. DR MassIVE; P50993; -. DR MaxQB; P50993; -. DR PaxDb; 9606-ENSP00000354490; -. DR PeptideAtlas; P50993; -. DR ProteomicsDB; 56274; -. DR Pumba; P50993; -. DR Antibodypedia; 34270; 204 antibodies from 27 providers. DR DNASU; 477; -. DR Ensembl; ENST00000361216.8; ENSP00000354490.3; ENSG00000018625.15. DR GeneID; 477; -. DR KEGG; hsa:477; -. DR MANE-Select; ENST00000361216.8; ENSP00000354490.3; NM_000702.4; NP_000693.1. DR UCSC; uc001fvc.4; human. DR AGR; HGNC:800; -. DR CTD; 477; -. DR DisGeNET; 477; -. DR GeneCards; ATP1A2; -. DR GeneReviews; ATP1A2; -. DR HGNC; HGNC:800; ATP1A2. DR HPA; ENSG00000018625; Group enriched (brain, skeletal muscle, tongue). DR MalaCards; ATP1A2; -. DR MIM; 104290; phenotype. DR MIM; 182340; gene. DR MIM; 602481; phenotype. DR MIM; 619602; phenotype. DR MIM; 619605; phenotype. DR neXtProt; NX_P50993; -. DR OpenTargets; ENSG00000018625; -. DR Orphanet; 2131; Alternating hemiplegia of childhood. DR Orphanet; 569; Familial or sporadic hemiplegic migraine. DR Orphanet; 442835; Non-specific early-onset epileptic encephalopathy. DR PharmGKB; PA30796; -. DR VEuPathDB; HostDB:ENSG00000018625; -. DR eggNOG; KOG0203; Eukaryota. DR GeneTree; ENSGT00940000159936; -. DR InParanoid; P50993; -. DR OMA; ISWEWAL; -. DR OrthoDB; 203629at2759; -. DR PhylomeDB; P50993; -. DR TreeFam; TF312838; -. DR PathwayCommons; P50993; -. DR Reactome; R-HSA-5578775; Ion homeostasis. DR Reactome; R-HSA-936837; Ion transport by P-type ATPases. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR SignaLink; P50993; -. DR BioGRID-ORCS; 477; 17 hits in 1148 CRISPR screens. DR ChiTaRS; ATP1A2; human. DR GeneWiki; ATP1A2; -. DR GenomeRNAi; 477; -. DR Pharos; P50993; Tclin. DR PRO; PR:P50993; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P50993; Protein. DR Bgee; ENSG00000018625; Expressed in lateral globus pallidus and 184 other cell types or tissues. DR ExpressionAtlas; P50993; baseline and differential. DR GO; GO:0005901; C:caveola; IEA:Ensembl. DR GO; GO:0042995; C:cell projection; ISS:ARUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl. DR GO; GO:0005768; C:endosome; IEA:Ensembl. DR GO; GO:1903561; C:extracellular vesicle; HDA:UniProtKB. DR GO; GO:0014704; C:intercalated disc; IEA:Ensembl. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0043025; C:neuronal cell body; ISS:ARUK-UCL. DR GO; GO:0031090; C:organelle membrane; IGI:ARUK-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005890; C:sodium:potassium-exchanging ATPase complex; IDA:BHF-UCL. DR GO; GO:0030315; C:T-tubule; IGI:ARUK-UCL. DR GO; GO:0005524; F:ATP binding; IMP:BHF-UCL. DR GO; GO:0016887; F:ATP hydrolysis activity; IMP:BHF-UCL. DR GO; GO:0019829; F:ATPase-coupled monoatomic cation transmembrane transporter activity; IDA:ARUK-UCL. DR GO; GO:0005391; F:P-type sodium:potassium-exchanging transporter activity; IDA:BHF-UCL. DR GO; GO:0016791; F:phosphatase activity; ISS:ARUK-UCL. DR GO; GO:0030955; F:potassium ion binding; IMP:BHF-UCL. DR GO; GO:0046982; F:protein heterodimerization activity; ISS:ARUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:BHF-UCL. DR GO; GO:0031402; F:sodium ion binding; IMP:BHF-UCL. DR GO; GO:0005496; F:steroid binding; IPI:BHF-UCL. DR GO; GO:1990239; F:steroid hormone binding; IDA:BHF-UCL. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:0021764; P:amygdala development; ISS:ARUK-UCL. DR GO; GO:0046034; P:ATP metabolic process; IMP:BHF-UCL. DR GO; GO:0001662; P:behavioral fear response; ISS:ARUK-UCL. DR GO; GO:0060048; P:cardiac muscle contraction; TAS:BHF-UCL. DR GO; GO:0086064; P:cell communication by electrical coupling involved in cardiac conduction; TAS:BHF-UCL. DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl. DR GO; GO:0071383; P:cellular response to steroid hormone stimulus; IDA:BHF-UCL. DR GO; GO:0030007; P:intracellular potassium ion homeostasis; IDA:BHF-UCL. DR GO; GO:0006883; P:intracellular sodium ion homeostasis; IDA:BHF-UCL. DR GO; GO:0040011; P:locomotion; ISS:ARUK-UCL. DR GO; GO:0035641; P:locomotory exploration behavior; ISS:ARUK-UCL. DR GO; GO:0086012; P:membrane depolarization during cardiac muscle cell action potential; TAS:BHF-UCL. DR GO; GO:0086009; P:membrane repolarization; TAS:BHF-UCL. DR GO; GO:0098655; P:monoatomic cation transmembrane transport; IDA:ARUK-UCL. DR GO; GO:1903170; P:negative regulation of calcium ion transmembrane transport; ISS:BHF-UCL. DR GO; GO:1903280; P:negative regulation of calcium:sodium antiporter activity; ISS:BHF-UCL. DR GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; ISS:ARUK-UCL. DR GO; GO:0045822; P:negative regulation of heart contraction; ISS:ARUK-UCL. DR GO; GO:0045988; P:negative regulation of striated muscle contraction; IEA:Ensembl. DR GO; GO:0001504; P:neurotransmitter uptake; ISS:ARUK-UCL. DR GO; GO:0021989; P:olfactory cortex development; ISS:ARUK-UCL. DR GO; GO:0045823; P:positive regulation of heart contraction; ISS:ARUK-UCL. DR GO; GO:1990573; P:potassium ion import across plasma membrane; IDA:BHF-UCL. DR GO; GO:0071805; P:potassium ion transmembrane transport; IGI:ARUK-UCL. DR GO; GO:0006813; P:potassium ion transport; NAS:UniProtKB. DR GO; GO:1902600; P:proton transmembrane transport; IBA:GO_Central. DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl. DR GO; GO:0086004; P:regulation of cardiac muscle cell contraction; IEA:Ensembl. DR GO; GO:0010881; P:regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion; TAS:BHF-UCL. DR GO; GO:0051946; P:regulation of glutamate uptake involved in transmission of nerve impulse; NAS:BHF-UCL. DR GO; GO:0006937; P:regulation of muscle contraction; ISS:ARUK-UCL. DR GO; GO:0002087; P:regulation of respiratory gaseous exchange by nervous system process; ISS:ARUK-UCL. DR GO; GO:0006940; P:regulation of smooth muscle contraction; IEA:Ensembl. DR GO; GO:0006942; P:regulation of striated muscle contraction; NAS:UniProtKB. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; NAS:BHF-UCL. DR GO; GO:0002026; P:regulation of the force of heart contraction; ISS:ARUK-UCL. DR GO; GO:0019229; P:regulation of vasoconstriction; IEA:Ensembl. DR GO; GO:0055119; P:relaxation of cardiac muscle; TAS:BHF-UCL. DR GO; GO:0010996; P:response to auditory stimulus; ISS:ARUK-UCL. DR GO; GO:1903416; P:response to glycoside; ISS:BHF-UCL. DR GO; GO:0035094; P:response to nicotine; IEA:Ensembl. DR GO; GO:0036376; P:sodium ion export across plasma membrane; IDA:BHF-UCL. DR GO; GO:0035725; P:sodium ion transmembrane transport; IGI:ARUK-UCL. DR GO; GO:0006814; P:sodium ion transport; NAS:UniProtKB. DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR CDD; cd02608; P-type_ATPase_Na-K_like; 1. DR Gene3D; 3.40.1110.10; Calcium-transporting ATPase, cytoplasmic domain N; 1. DR Gene3D; 2.70.150.10; Calcium-transporting ATPase, cytoplasmic transduction domain A; 1. DR Gene3D; 1.20.1110.10; Calcium-transporting ATPase, transmembrane domain; 1. DR Gene3D; 3.40.50.1000; HAD superfamily/HAD-like; 1. DR InterPro; IPR006068; ATPase_P-typ_cation-transptr_C. DR InterPro; IPR004014; ATPase_P-typ_cation-transptr_N. DR InterPro; IPR023299; ATPase_P-typ_cyto_dom_N. DR InterPro; IPR018303; ATPase_P-typ_P_site. DR InterPro; IPR023298; ATPase_P-typ_TM_dom_sf. DR InterPro; IPR008250; ATPase_P-typ_transduc_dom_A_sf. DR InterPro; IPR036412; HAD-like_sf. DR InterPro; IPR023214; HAD_sf. DR InterPro; IPR005775; P-type_ATPase_IIC. DR InterPro; IPR001757; P_typ_ATPase. DR InterPro; IPR044492; P_typ_ATPase_HD_dom. DR NCBIfam; TIGR01106; ATPase-IIC_X-K; 1. DR NCBIfam; TIGR01494; ATPase_P-type; 2. DR PANTHER; PTHR43294; SODIUM/POTASSIUM-TRANSPORTING ATPASE SUBUNIT ALPHA; 1. DR PANTHER; PTHR43294:SF6; SODIUM_POTASSIUM-TRANSPORTING ATPASE SUBUNIT ALPHA-2; 1. DR Pfam; PF13246; Cation_ATPase; 1. DR Pfam; PF00689; Cation_ATPase_C; 1. DR Pfam; PF00690; Cation_ATPase_N; 1. DR Pfam; PF00122; E1-E2_ATPase; 1. DR Pfam; PF00702; Hydrolase; 1. DR PRINTS; PR00119; CATATPASE. DR PRINTS; PR00121; NAKATPASE. DR SFLD; SFLDS00003; Haloacid_Dehalogenase; 1. DR SFLD; SFLDF00027; p-type_atpase; 1. DR SMART; SM00831; Cation_ATPase_N; 1. DR SUPFAM; SSF81653; Calcium ATPase, transduction domain A; 1. DR SUPFAM; SSF81665; Calcium ATPase, transmembrane domain M; 1. DR SUPFAM; SSF56784; HAD-like; 1. DR SUPFAM; SSF81660; Metal cation-transporting ATPase, ATP-binding domain N; 1. DR PROSITE; PS00154; ATPASE_E1_E2; 1. DR Genevisible; P50993; HS. PE 1: Evidence at protein level; KW ATP-binding; Cell membrane; Disease variant; Epilepsy; KW Intellectual disability; Ion transport; Magnesium; Membrane; Metal-binding; KW Nucleotide-binding; Phosphoprotein; Potassium; Potassium transport; KW Reference proteome; Sodium; Sodium transport; Sodium/potassium transport; KW Translocase; Transmembrane; Transmembrane helix; Transport. FT PROPEP 1..5 FT /evidence="ECO:0000250" FT /id="PRO_0000002503" FT CHAIN 6..1020 FT /note="Sodium/potassium-transporting ATPase subunit alpha- FT 2" FT /id="PRO_0000002504" FT TOPO_DOM 6..85 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 86..106 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 107..129 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 130..150 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 151..286 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 287..306 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 307..318 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 319..336 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 337..769 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 770..789 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 790..799 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 800..820 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 821..840 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 841..863 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 864..915 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 916..935 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 936..948 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 949..967 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 968..982 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 983..1003 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1004..1020 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 1..31 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 80..82 FT /note="Interaction with phosphoinositide-3 kinase" FT /evidence="ECO:0000250" FT REGION 212..231 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 212..230 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 374 FT /note="4-aspartylphosphate intermediate" FT /evidence="ECO:0000250" FT BINDING 714 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250" FT BINDING 718 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250" FT MOD_RES 10 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6PIE5" FT MOD_RES 439 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P06686" FT MOD_RES 450 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6PIE5" FT MOD_RES 496 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P06686" FT MOD_RES 559 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6PIE5" FT MOD_RES 570 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 587 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 672 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6PIE5" FT MOD_RES 826 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P09626" FT MOD_RES 940 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250" FT VARIANT 293 FT /note="I -> M (in DEE98; decreased FT sodium/potassium-exchanging ATPase activity; decreased FT affinity for sodium ions; dbSNP:rs1553244746)" FT /evidence="ECO:0000269|PubMed:33880529" FT /id="VAR_086441" FT VARIANT 341 FT /note="C -> F (in DEE98; dbSNP:rs1057521630)" FT /evidence="ECO:0000269|PubMed:33880529" FT /id="VAR_086442" FT VARIANT 366 FT /note="G -> A (in DEE98; decreased affinity for sodium FT ions; decreased affinity for potassium ions; FT dbSNP:rs1057518514)" FT /evidence="ECO:0000269|PubMed:27864847, FT ECO:0000269|PubMed:33880529" FT /id="VAR_078231" FT VARIANT 378 FT /note="T -> N (in AHC1; dbSNP:rs28934002)" FT /evidence="ECO:0000269|PubMed:15174025" FT /id="VAR_019934" FT VARIANT 593 FT /note="R -> Q (found in a patient with generalized FT tonic-clonic seizures; likely pathogenic; decreased FT sodium/potassium-exchanging ATPase activity; FT dbSNP:rs1553245178)" FT /evidence="ECO:0000269|PubMed:33880529" FT /id="VAR_086443" FT VARIANT 593 FT /note="R -> W (in DEE98; dbSNP:rs886039530)" FT /evidence="ECO:0000269|PubMed:27864847" FT /id="VAR_078232" FT VARIANT 689 FT /note="R -> Q (in FHM2; dbSNP:rs28933401)" FT /evidence="ECO:0000269|PubMed:12953268" FT /id="VAR_019935" FT VARIANT 715 FT /note="G -> R (in FHM2; de novo mutation in a sporadic FT case; dbSNP:rs1553245771)" FT /evidence="ECO:0000269|PubMed:21352219" FT /id="VAR_065685" FT VARIANT 731 FT /note="M -> T (in FHM2; dbSNP:rs28933400)" FT /evidence="ECO:0000269|PubMed:12953268" FT /id="VAR_019936" FT VARIANT 764 FT /note="L -> P (in FHM2; loss of function; FT dbSNP:rs28933398)" FT /evidence="ECO:0000269|PubMed:12539047" FT /id="VAR_019937" FT VARIANT 874 FT /note="G -> S (in FHM2; some patients exhibit a clinical FT overlap between migraine and epilepsy; dbSNP:rs1651959213)" FT /evidence="ECO:0000269|PubMed:23918834" FT /id="VAR_069991" FT VARIANT 887 FT /note="W -> R (in FHM2; loss of function; FT dbSNP:rs28933399)" FT /evidence="ECO:0000269|PubMed:12539047" FT /id="VAR_019938" FT VARIANT 908 FT /note="R -> Q (in DEE98; decreased FT sodium/potassium-exchanging ATPase activity)" FT /evidence="ECO:0000269|PubMed:33880529" FT /id="VAR_086444" FT VARIANT 957..1020 FT /note="Missing (in FARIMPD; uncertain significance)" FT /evidence="ECO:0000269|PubMed:31608932" FT /id="VAR_086445" FT VARIANT 1007 FT /note="R -> W (in FHM2; some patients exhibit a clinical FT overlap between migraine and epilepsy; dbSNP:rs746795369)" FT /evidence="ECO:0000269|PubMed:23838748" FT /id="VAR_069992" SQ SEQUENCE 1020 AA; 112265 MW; AFBD8EA94FFB4FC3 CRC64; MGRGAGREYS PAATTAENGG GKKKQKEKEL DELKKEVAMD DHKLSLDELG RKYQVDLSKG LTNQRAQDVL ARDGPNALTP PPTTPEWVKF CRQLFGGFSI LLWIGAILCF LAYGIQAAME DEPSNDNLYL GVVLAAVVIV TGCFSYYQEA KSSKIMDSFK NMVPQQALVI REGEKMQINA EEVVVGDLVE VKGGDRVPAD LRIISSHGCK VDNSSLTGES EPQTRSPEFT HENPLETRNI CFFSTNCVEG TARGIVIATG DRTVMGRIAT LASGLEVGRT PIAMEIEHFI QLITGVAVFL GVSFFVLSLI LGYSWLEAVI FLIGIIVANV PEGLLATVTV CLTLTAKRMA RKNCLVKNLE AVETLGSTST ICSDKTGTLT QNRMTVAHMW FDNQIHEADT TEDQSGATFD KRSPTWTALS RIAGLCNRAV FKAGQENISV SKRDTAGDAS ESALLKCIEL SCGSVRKMRD RNPKVAEIPF NSTNKYQLSI HEREDSPQSH VLVMKGAPER ILDRCSTILV QGKEIPLDKE MQDAFQNAYM ELGGLGERVL GFCQLNLPSG KFPRGFKFDT DELNFPTEKL CFVGLMSMID PPRAAVPDAV GKCRSAGIKV IMVTGDHPIT AKAIAKGVGI ISEGNETVED IAARLNIPMS QVNPREAKAC VVHGSDLKDM TSEQLDEILK NHTEIVFART SPQQKLIIVE GCQRQGAIVA VTGDGVNDSP ALKKADIGIA MGISGSDVSK QAADMILLDD NFASIVTGVE EGRLIFDNLK KSIAYTLTSN IPEITPFLLF IIANIPLPLG TVTILCIDLG TDMVPAISLA YEAAESDIMK RQPRNSQTDK LVNERLISMA YGQIGMIQAL GGFFTYFVIL AENGFLPSRL LGIRLDWDDR TMNDLEDSYG QEWTYEQRKV VEFTCHTAFF ASIVVVQWAD LIICKTRRNS VFQQGMKNKI LIFGLLEETA LAAFLSYCPG MGVALRMYPL KVTWWFCAFP YSLLIFIYDE VRKLILRRYP GGWVEKETYY //