ID PLM_HUMAN Reviewed; 92 AA. AC O00168; A8K196; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 30-AUG-2002, sequence version 2. DT 13-FEB-2019, entry version 153. DE RecName: Full=Phospholemman {ECO:0000250|UniProtKB:P56513}; DE AltName: Full=FXYD domain-containing ion transport regulator 1 {ECO:0000312|HGNC:HGNC:4025}; DE AltName: Full=Sodium/potassium-transporting ATPase subunit FXYD1 {ECO:0000305}; DE Flags: Precursor; GN Name=FXYD1 {ECO:0000312|HGNC:HGNC:4025}; GN Synonyms=PLM {ECO:0000303|PubMed:9169143}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Heart; RX PubMed=9169143; DOI=10.1006/geno.1997.4665; RA Chen L.-S.K., Lo C.F., Numann R., Cuddy M.; RT "Characterization of the human and rat phospholemman (PLM) cDNAs and RT localization of the human PLM gene to chromosome 19q13.1."; RL Genomics 41:435-443(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10950925; DOI=10.1006/geno.2000.6274; RA Sweadner K.J., Rael E.; RT "The FXYD gene family of small ion transport regulators or channels: RT cDNA sequence, protein signature sequence, and expression."; RL Genomics 68:41-56(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, Lung, and Testis; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP PHOSPHORYLATION BY DMPK. RX PubMed=10811636; DOI=10.1074/jbc.M000899200; RA Mounsey J.P., John J.E. III, Helmke S.M., Bush E.W., Gilbert J., RA Roses A.D., Perryman M.B., Jones L.R., Moorman J.R.; RT "Phospholemman is a substrate for myotonic dystrophy protein kinase."; RL J. Biol. Chem. 275:23362-23367(2000). RN [6] RP SUBUNIT. RX PubMed=16597826; DOI=10.1110/ps.051899406; RA Beevers A.J., Kukol A.; RT "Secondary structure, orientation, and oligomerization of RT phospholemman, a cardiac transmembrane protein."; RL Protein Sci. 15:1127-1132(2006). RN [7] RP PALMITOYLATION AT CYS-60 AND CYS-62, PHOSPHORYLATION AT SER-88, AND RP MUTAGENESIS OF CYS-60 AND CYS-62. RX PubMed=21868384; DOI=10.1074/jbc.M111.282145; RA Tulloch L.B., Howie J., Wypijewski K.J., Wilson C.R., Bernard W.G., RA Shattock M.J., Fuller W.; RT "The inhibitory effect of phospholemman on the sodium pump requires RT its palmitoylation."; RL J. Biol. Chem. 286:36020-36031(2011). RN [8] RP STRUCTURE BY NMR OF 21-92, AND SUBUNIT. RX PubMed=17511473; DOI=10.1021/bi700391b; RA Teriete P., Franzin C.M., Choi J., Marassi F.M.; RT "Structure of the Na,K-ATPase regulatory protein FXYD1 in micelles."; RL Biochemistry 46:6774-6783(2007). CC -!- FUNCTION: Associates with and regulates the activity of the CC sodium/potassium-transporting ATPase (NKA) which transports Na(+) CC out of the cell and K(+) into the cell. Inhibits NKA activity in CC its unphosphorylated state and stimulates activity when CC phosphorylated. Reduces glutathionylation of the NKA beta-1 CC subunit ATP1B1, thus reversing glutathionylation-mediated CC inhibition of ATP1B1. Contributes to female sexual development by CC maintaining the excitability of neurons which secrete CC gonadotropin-releasing hormone. {ECO:0000250|UniProtKB:O08589, CC ECO:0000250|UniProtKB:P56513, ECO:0000250|UniProtKB:Q9Z239}. CC -!- SUBUNIT: Homotetramer (PubMed:16597826). Monomer CC (PubMed:17511473). Regulatory subunit of the sodium/potassium- CC transporting ATPase (NKA) which is composed of a catalytic alpha CC subunit, an auxiliary non-catalytic beta subunit and an additional CC regulatory subunit (By similarity). The monomeric form associates CC with NKA while the oligomeric form does not (By similarity). CC Interacts with the catalytic alpha-1 subunit ATP1A1 (By CC similarity). Also interacts with the catalytic alpha-2 and alpha-3 CC subunits ATP1A2 and ATP1A3 (By similarity). Very little CC interaction with ATP1A1, ATP1A2 or ATP1A3 when phosphorylated at CC Ser-83 (By similarity). Interacts with the non-catalytic beta-1 CC subunit ATP1B1 (By similarity). Oxidative stress decreases CC interaction with ATP1A1 but increases interaction with ATP1B1 (By CC similarity). {ECO:0000250|UniProtKB:O08589, CC ECO:0000250|UniProtKB:P56513, ECO:0000250|UniProtKB:Q3SZX0, CC ECO:0000250|UniProtKB:Q9Z239, ECO:0000269|PubMed:16597826, CC ECO:0000269|PubMed:17511473}. CC -!- SUBCELLULAR LOCATION: Cell membrane, sarcolemma CC {ECO:0000250|UniProtKB:P56513}; Single-pass type I membrane CC protein {ECO:0000255}. Apical cell membrane CC {ECO:0000250|UniProtKB:O08589}; Single-pass type I membrane CC protein {ECO:0000255}. Membrane, caveola CC {ECO:0000250|UniProtKB:O08589}. Cell membrane, sarcolemma, T- CC tubule {ECO:0000250|UniProtKB:O08589}. Note=Detected in the apical CC cell membrane in brain. In myocytes, localizes to sarcolemma, t- CC tubules and intercalated disks. {ECO:0000250|UniProtKB:O08589}. CC -!- TISSUE SPECIFICITY: Highest expression in skeletal muscle and CC heart. Moderate levels in brain, placenta, lung, liver, pancreas, CC uterus, bladder, prostate, small intestine and colon with mucosal CC lining. Very low levels in kidney, colon and small intestine CC without mucosa, prostate without endothelial lining, spleen, and CC testis. {ECO:0000269|PubMed:9169143}. CC -!- DOMAIN: The cytoplasmic domain is sufficient to regulate CC sodium/potassium-transporting ATPase activity. CC {ECO:0000250|UniProtKB:O08589}. CC -!- PTM: Major plasma membrane substrate for cAMP-dependent protein CC kinase (PKA) and protein kinase C (PKC) in several different CC tissues (By similarity). Phosphorylated in response to insulin and CC adrenergic stimulation (By similarity). Phosphorylation at Ser-88 CC stimulates sodium/potassium-transporting ATPase activity while the CC unphosphorylated form inhibits sodium/potassium-transporting CC ATPase activity (By similarity). Phosphorylation increases CC tetramerization, decreases binding to ATP1A1 and reduces CC inhibition of ATP1A1 activity (By similarity). Phosphorylation at CC Ser-83 leads to greatly reduced interaction with ATP1A1, ATP1A2 CC and ATP1A3 (By similarity). May be phosphorylated by DMPK CC (PubMed:10811636). {ECO:0000250|UniProtKB:O08589, CC ECO:0000250|UniProtKB:P56513, ECO:0000269|PubMed:10811636}. CC -!- PTM: Palmitoylation increases half-life and stability and is CC enhanced upon phosphorylation at Ser-88 by PKA. CC {ECO:0000269|PubMed:21868384}. CC -!- SIMILARITY: Belongs to the FXYD family. {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; U72245; AAC51286.1; -; mRNA. DR EMBL; AK289811; BAF82500.1; -; mRNA. DR EMBL; BC032800; AAH32800.1; -; mRNA. DR CCDS; CCDS12445.1; -. DR RefSeq; NP_001265646.1; NM_001278717.1. DR RefSeq; NP_001265647.1; NM_001278718.1. DR RefSeq; NP_005022.2; NM_005031.4. DR RefSeq; NP_068702.1; NM_021902.3. DR RefSeq; XP_016882363.1; XM_017026874.1. DR UniGene; Hs.442498; -. DR PDB; 2J1I; Model; -; A/B/C/D=32-59. DR PDB; 2JO1; NMR; -; A=21-92. DR PDBsum; 2J1I; -. DR PDBsum; 2JO1; -. DR ProteinModelPortal; O00168; -. DR SMR; O00168; -. DR BioGrid; 111363; 16. DR STRING; 9606.ENSP00000343314; -. DR iPTMnet; O00168; -. DR PhosphoSitePlus; O00168; -. DR SwissPalm; O00168; -. DR BioMuta; FXYD1; -. DR jPOST; O00168; -. DR MaxQB; O00168; -. DR PaxDb; O00168; -. DR PeptideAtlas; O00168; -. DR PRIDE; O00168; -. DR ProteomicsDB; 47759; -. DR DNASU; 5348; -. DR Ensembl; ENST00000351325; ENSP00000343314; ENSG00000266964. DR Ensembl; ENST00000455515; ENSP00000393611; ENSG00000266964. DR Ensembl; ENST00000588081; ENSP00000467727; ENSG00000266964. DR Ensembl; ENST00000588607; ENSP00000468535; ENSG00000266964. DR Ensembl; ENST00000588715; ENSP00000465289; ENSG00000266964. DR Ensembl; ENST00000589209; ENSP00000466398; ENSG00000266964. DR Ensembl; ENST00000612146; ENSP00000481244; ENSG00000266964. DR GeneID; 5348; -. DR KEGG; hsa:5348; -. DR UCSC; uc002nyc.5; human. DR CTD; 5348; -. DR DisGeNET; 5348; -. DR EuPathDB; HostDB:ENSG00000266964.5; -. DR GeneCards; FXYD1; -. DR HGNC; HGNC:4025; FXYD1. DR HPA; HPA026873; -. DR MIM; 602359; gene. DR neXtProt; NX_O00168; -. DR OpenTargets; ENSG00000266964; -. DR PharmGKB; PA28441; -. DR eggNOG; ENOG410J08K; Eukaryota. DR eggNOG; ENOG410YYN6; LUCA. DR GeneTree; ENSGT00940000153062; -. DR HOGENOM; HOG000234467; -. DR HOVERGEN; HBG008212; -. DR InParanoid; O00168; -. DR KO; K13360; -. DR OrthoDB; 1621616at2759; -. DR PhylomeDB; O00168; -. DR TreeFam; TF333443; -. DR Reactome; R-HSA-5578775; Ion homeostasis. DR Reactome; R-HSA-936837; Ion transport by P-type ATPases. DR SIGNOR; O00168; -. DR EvolutionaryTrace; O00168; -. DR GeneWiki; FXYD1; -. DR GenomeRNAi; 5348; -. DR PRO; PR:O00168; -. DR Proteomes; UP000005640; Chromosome 19. DR Bgee; ENSG00000266964; Expressed in 90 organ(s), highest expression level in tibial nerve. DR ExpressionAtlas; O00168; baseline and differential. DR Genevisible; O00168; HS. DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB. DR GO; GO:0005901; C:caveola; ISS:UniProtKB. DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc. DR GO; GO:0014704; C:intercalated disc; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0042383; C:sarcolemma; ISS:UniProtKB. DR GO; GO:0005890; C:sodium:potassium-exchanging ATPase complex; ISS:UniProtKB. DR GO; GO:0030315; C:T-tubule; ISS:UniProtKB. DR GO; GO:0005254; F:chloride channel activity; TAS:ProtInc. DR GO; GO:0044325; F:ion channel binding; ISS:BHF-UCL. DR GO; GO:0099106; F:ion channel regulator activity; IEA:InterPro. DR GO; GO:0017080; F:sodium channel regulator activity; ISS:BHF-UCL. DR GO; GO:0006821; P:chloride transport; TAS:ProtInc. DR GO; GO:0006936; P:muscle contraction; TAS:ProtInc. DR GO; GO:0010734; P:negative regulation of protein glutathionylation; ISS:UniProtKB. DR GO; GO:1903278; P:positive regulation of sodium ion export across plasma membrane; ISS:UniProtKB. DR GO; GO:0006813; P:potassium ion transport; IEA:UniProtKB-KW. DR GO; GO:0086036; P:regulation of cardiac muscle cell membrane potential; ISS:BHF-UCL. DR GO; GO:0008016; P:regulation of heart contraction; TAS:BHF-UCL. DR GO; GO:2000649; P:regulation of sodium ion transmembrane transporter activity; ISS:BHF-UCL. DR GO; GO:0006814; P:sodium ion transport; IEA:UniProtKB-KW. DR InterPro; IPR000272; Ion-transport_regulator_FXYD. DR Pfam; PF02038; ATP1G1_PLM_MAT8; 1. DR ProDom; PD005989; PD005989; 1. DR PROSITE; PS01310; FXYD; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Complete proteome; Glutathionylation; KW Ion transport; Lipoprotein; Membrane; Palmitate; Phosphoprotein; KW Potassium; Potassium transport; Reference proteome; Signal; Sodium; KW Sodium transport; Sodium/potassium transport; Transmembrane; KW Transmembrane helix; Transport. FT SIGNAL 1 20 {ECO:0000250|UniProtKB:P56513}. FT CHAIN 21 92 Phospholemman. FT /FTId=PRO_0000010359. FT TOPO_DOM 21 35 Extracellular. {ECO:0000255}. FT TRANSMEM 36 56 Helical. {ECO:0000255}. FT TOPO_DOM 57 92 Cytoplasmic. {ECO:0000255}. FT MOD_RES 62 62 S-glutathionyl cysteine; alternate. FT {ECO:0000250|UniProtKB:P56513}. FT MOD_RES 79 79 Phosphothreonine. FT {ECO:0000250|UniProtKB:Q9Z239}. FT MOD_RES 82 82 Phosphoserine. FT {ECO:0000250|UniProtKB:Q9Z239}. FT MOD_RES 83 83 Phosphoserine; by PKA and PKC. FT {ECO:0000250|UniProtKB:P56513}. FT MOD_RES 88 88 Phosphoserine; by PKA. FT {ECO:0000269|PubMed:21868384}. FT MOD_RES 89 89 Phosphothreonine; by PKC. FT {ECO:0000250|UniProtKB:P56513}. FT LIPID 60 60 S-palmitoyl cysteine. FT {ECO:0000269|PubMed:21868384}. FT LIPID 62 62 S-palmitoyl cysteine; alternate. FT {ECO:0000269|PubMed:21868384}. FT MUTAGEN 60 60 C->S: Significantly reduced half-life; FT when associated with S-62. FT {ECO:0000269|PubMed:21868384}. FT MUTAGEN 62 62 C->S: Significantly reduced half-life; FT when associated with S-60. FT {ECO:0000269|PubMed:21868384}. FT CONFLICT 3 3 S -> P (in Ref. 1; AAC51286). FT {ECO:0000305}. FT CONFLICT 5 5 G -> H (in Ref. 1; AAC51286). FT {ECO:0000305}. FT HELIX 23 26 {ECO:0000244|PDB:2JO1}. FT HELIX 28 30 {ECO:0000244|PDB:2JO1}. FT HELIX 34 64 {ECO:0000244|PDB:2JO1}. FT TURN 66 68 {ECO:0000244|PDB:2JO1}. FT STRAND 69 71 {ECO:0000244|PDB:2JO1}. FT TURN 75 77 {ECO:0000244|PDB:2JO1}. FT HELIX 80 89 {ECO:0000244|PDB:2JO1}. SQ SEQUENCE 92 AA; 10441 MW; 11602EFEAFFD8BD8 CRC64; MASLGHILVF CVGLLTMAKA ESPKEHDPFT YDYQSLQIGG LVIAGILFIL GILIVLSRRC RCKFNQQQRT GEPDEEEGTF RSSIRRLSTR RR //