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 09-APR-2025, entry version 187. 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; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC 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: cDNA RT 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., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., 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., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA 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 project: RT 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 phospholemman, a RT 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 its RT 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(+) out CC of the cell and K(+) into the cell. Inhibits NKA activity in its CC unphosphorylated state and stimulates activity when phosphorylated. CC Reduces glutathionylation of the NKA beta-1 subunit ATP1B1, thus CC reversing glutathionylation-mediated inhibition of ATP1B1. Contributes CC to female sexual development by maintaining the excitability of neurons CC which secrete gonadotropin-releasing hormone. CC {ECO:0000250|UniProtKB:O08589, ECO:0000250|UniProtKB:P56513, CC ECO:0000250|UniProtKB:Q9Z239}. CC -!- SUBUNIT: Homotetramer (PubMed:16597826). Monomer (PubMed:17511473). CC Regulatory subunit of the sodium/potassium-transporting ATPase (NKA) CC which is composed of a catalytic alpha subunit, an auxiliary non- CC catalytic beta subunit and an additional regulatory subunit (By CC similarity). The monomeric form associates with NKA while the CC oligomeric form does not (By similarity). Interacts with the catalytic CC alpha-1 subunit ATP1A1 (By similarity). Also interacts with the CC catalytic alpha-2 and alpha-3 subunits ATP1A2 and ATP1A3 (By CC similarity). Very little interaction with ATP1A1, ATP1A2 or ATP1A3 when CC phosphorylated at Ser-83 (By similarity). Interacts with the non- CC catalytic beta-1 subunit ATP1B1 (By similarity). Oxidative stress CC decreases interaction with ATP1A1 but increases interaction with ATP1B1 CC (By 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 protein CC {ECO:0000255}. Apical cell membrane {ECO:0000250|UniProtKB:O08589}; CC Single-pass type I membrane protein {ECO:0000255}. Membrane, caveola CC {ECO:0000250|UniProtKB:O08589}. Cell membrane, sarcolemma, T-tubule CC {ECO:0000250|UniProtKB:O08589}. Note=Detected in the apical cell CC membrane in brain. In myocytes, localizes to sarcolemma, t-tubules and CC intercalated disks. {ECO:0000250|UniProtKB:O08589}. CC -!- TISSUE SPECIFICITY: Highest expression in skeletal muscle and heart. CC Moderate levels in brain, placenta, lung, liver, pancreas, uterus, CC bladder, prostate, small intestine and colon with mucosal lining. Very CC low levels in kidney, colon and small intestine without mucosa, CC prostate without endothelial lining, spleen, and testis. CC {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 kinase CC (PKA) and protein kinase C (PKC) in several different tissues (By CC similarity). Phosphorylated in response to insulin and adrenergic CC stimulation (By similarity). Phosphorylation at Ser-88 stimulates CC sodium/potassium-transporting ATPase activity while the CC unphosphorylated form inhibits sodium/potassium-transporting ATPase CC activity (By similarity). Phosphorylation increases tetramerization, CC decreases binding to ATP1A1 and reduces inhibition of ATP1A1 activity CC (By similarity). Phosphorylation at Ser-83 leads to greatly reduced CC interaction with ATP1A1, ATP1A2 and ATP1A3 (By similarity). May be CC phosphorylated by DMPK (PubMed:10811636). CC {ECO:0000250|UniProtKB:O08589, ECO:0000250|UniProtKB:P56513, CC ECO:0000269|PubMed:10811636}. CC -!- PTM: Palmitoylation increases half-life and stability and is enhanced CC upon phosphorylation at Ser-88 by PKA. {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_001278717.2. DR RefSeq; NP_001265647.1; NM_001278718.2. DR RefSeq; NP_005022.2; NM_005031.4. DR RefSeq; NP_068702.1; NM_021902.4. DR RefSeq; XP_016882363.1; XM_017026874.3. DR RefSeq; XP_047294894.1; XM_047438938.1. DR RefSeq; XP_054177194.1; XM_054321219.1. DR RefSeq; XP_054177195.1; XM_054321220.1. DR PDB; 2JO1; NMR; -; A=21-92. DR PDBsum; 2JO1; -. DR AlphaFoldDB; O00168; -. DR BMRB; O00168; -. DR SMR; O00168; -. DR BioGRID; 111363; 29. DR ComplexPortal; CPX-8009; Sodium:potassium-exchanging ATPase complex, FXYD1 variant. DR IntAct; O00168; 12. DR STRING; 9606.ENSP00000481244; -. DR TCDB; 1.A.27.1.8; the phospholemman (plm) family. DR iPTMnet; O00168; -. DR PhosphoSitePlus; O00168; -. DR SwissPalm; O00168; -. DR BioMuta; FXYD1; -. DR MassIVE; O00168; -. DR PaxDb; 9606-ENSP00000481244; -. DR PeptideAtlas; O00168; -. DR ProteomicsDB; 47759; -. DR Antibodypedia; 65378; 401 antibodies from 31 providers. DR DNASU; 5348; -. DR Ensembl; ENST00000351325.9; ENSP00000343314.3; ENSG00000266964.6. DR Ensembl; ENST00000455515.6; ENSP00000393611.1; ENSG00000266964.6. DR Ensembl; ENST00000588081.5; ENSP00000467727.1; ENSG00000266964.6. DR Ensembl; ENST00000588607.5; ENSP00000468535.1; ENSG00000266964.6. DR Ensembl; ENST00000588715.5; ENSP00000465289.1; ENSG00000266964.6. DR Ensembl; ENST00000589209.5; ENSP00000466398.1; ENSG00000266964.6. DR Ensembl; ENST00000612146.4; ENSP00000481244.1; ENSG00000266964.6. DR GeneID; 5348; -. DR KEGG; hsa:5348; -. DR MANE-Select; ENST00000351325.9; ENSP00000343314.3; NM_021902.4; NP_068702.1. DR UCSC; uc002nyc.5; human. DR AGR; HGNC:4025; -. DR CTD; 5348; -. DR DisGeNET; 5348; -. DR GeneCards; FXYD1; -. DR HGNC; HGNC:4025; FXYD1. DR HPA; ENSG00000266964; Tissue enhanced (choroid plexus, skeletal muscle). DR MIM; 602359; gene. DR neXtProt; NX_O00168; -. DR OpenTargets; ENSG00000266964; -. DR PharmGKB; PA28441; -. DR VEuPathDB; HostDB:ENSG00000266964; -. DR eggNOG; ENOG502S5XM; Eukaryota. DR GeneTree; ENSGT00940000153062; -. DR HOGENOM; CLU_171208_2_0_1; -. DR InParanoid; O00168; -. DR OMA; PFNYDYH; -. DR OrthoDB; 8430468at2759; -. DR PhylomeDB; O00168; -. DR TreeFam; TF333443; -. DR PathwayCommons; O00168; -. 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; O00168; -. DR SIGNOR; O00168; -. DR BioGRID-ORCS; 5348; 20 hits in 1146 CRISPR screens. DR ChiTaRS; FXYD1; human. DR EvolutionaryTrace; O00168; -. DR GeneWiki; FXYD1; -. DR GenomeRNAi; 5348; -. DR Pharos; O00168; Tbio. DR PRO; PR:O00168; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; O00168; protein. DR Bgee; ENSG00000266964; Expressed in hindlimb stylopod muscle and 95 other cell types or tissues. DR ExpressionAtlas; O00168; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB. DR GO; GO:0005901; C:caveola; ISS:UniProtKB. 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:0017080; F:sodium channel regulator activity; ISS:BHF-UCL. DR GO; GO:0044325; F:transmembrane transporter binding; 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 CDD; cd20317; FXYD1; 1. DR FunFam; 1.20.5.780:FF:000002; FXYD domain-containing ion transport regulator; 1. DR Gene3D; 1.20.5.780; Single helix bin; 1. DR InterPro; IPR047297; FXYD_motif. DR InterPro; IPR000272; Ion-transport_regulator_FXYD. DR InterPro; IPR047281; PLM. DR PANTHER; PTHR14132:SF12; PHOSPHOLEMMAN; 1. DR PANTHER; PTHR14132; SODIUM/POTASSIUM-TRANSPORTING ATPASE SUBUNIT GAMMA; 1. DR Pfam; PF02038; ATP1G1_PLM_MAT8; 1. DR PROSITE; PS01310; FXYD; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Glutathionylation; Ion transport; Lipoprotein; KW Membrane; Palmitate; Phosphoprotein; Potassium; Potassium transport; KW Proteomics identification; Reference proteome; Signal; Sodium; KW Sodium transport; Sodium/potassium transport; Transmembrane; KW Transmembrane helix; Transport. FT SIGNAL 1..20 FT /evidence="ECO:0000250|UniProtKB:P56513" FT CHAIN 21..92 FT /note="Phospholemman" FT /id="PRO_0000010359" FT TOPO_DOM 21..35 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 36..56 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 57..92 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 65..92 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 83..92 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 62 FT /note="S-glutathionyl cysteine; alternate" FT /evidence="ECO:0000250|UniProtKB:P56513" FT MOD_RES 79 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q9Z239" FT MOD_RES 82 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Z239" FT MOD_RES 83 FT /note="Phosphoserine; by PKA and PKC" FT /evidence="ECO:0000250|UniProtKB:P56513" FT MOD_RES 88 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:21868384" FT MOD_RES 89 FT /note="Phosphothreonine; by PKC" FT /evidence="ECO:0000250|UniProtKB:P56513" FT LIPID 60 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:21868384" FT LIPID 62 FT /note="S-palmitoyl cysteine; alternate" FT /evidence="ECO:0000269|PubMed:21868384" FT MUTAGEN 60 FT /note="C->S: Significantly reduced half-life; when FT associated with S-62." FT /evidence="ECO:0000269|PubMed:21868384" FT MUTAGEN 62 FT /note="C->S: Significantly reduced half-life; when FT associated with S-60." FT /evidence="ECO:0000269|PubMed:21868384" FT CONFLICT 3 FT /note="S -> P (in Ref. 1; AAC51286)" FT /evidence="ECO:0000305" FT CONFLICT 5 FT /note="G -> H (in Ref. 1; AAC51286)" FT /evidence="ECO:0000305" FT HELIX 23..26 FT /evidence="ECO:0007829|PDB:2JO1" FT HELIX 28..30 FT /evidence="ECO:0007829|PDB:2JO1" FT HELIX 34..64 FT /evidence="ECO:0007829|PDB:2JO1" FT TURN 66..68 FT /evidence="ECO:0007829|PDB:2JO1" FT STRAND 69..71 FT /evidence="ECO:0007829|PDB:2JO1" FT TURN 75..77 FT /evidence="ECO:0007829|PDB:2JO1" FT HELIX 80..89 FT /evidence="ECO:0007829|PDB:2JO1" SQ SEQUENCE 92 AA; 10441 MW; 11602EFEAFFD8BD8 CRC64; MASLGHILVF CVGLLTMAKA ESPKEHDPFT YDYQSLQIGG LVIAGILFIL GILIVLSRRC RCKFNQQQRT GEPDEEEGTF RSSIRRLSTR RR //