ID PLM_CANLF Reviewed; 92 AA. AC P56513; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 15-JUL-1998, sequence version 1. DT 08-MAY-2019, entry version 99. DE RecName: Full=Phospholemman {ECO:0000303|PubMed:1710217}; DE AltName: Full=FXYD domain-containing ion transport regulator 1 {ECO:0000250|UniProtKB:O00168}; DE AltName: Full=Sodium/potassium-transporting ATPase subunit FXYD1 {ECO:0000305}; DE Flags: Precursor; GN Name=FXYD1 {ECO:0000250|UniProtKB:O00168}; GN Synonyms=PLM {ECO:0000250|UniProtKB:O00168}; OS Canis lupus familiaris (Dog) (Canis familiaris). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; OC Canis. OX NCBI_TaxID=9615; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 21-92, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION. RC TISSUE=Heart ventricle; RX PubMed=1710217; RA Palmer C.J., Scott B.T., Jones L.R.; RT "Purification and complete sequence determination of the major plasma RT membrane substrate for cAMP-dependent protein kinase and protein RT kinase C in myocardium."; RL J. Biol. Chem. 266:11126-11130(1991). RN [2] RP SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=9486665; RA Chen Z., Jones L.R., O'Brian J.J., Moorman J.R., Cala S.E.; RT "Structural domains in phospholemman: a possible role for the carboxyl RT terminus in channel inactivation."; RL Circ. Res. 82:367-374(1998). RN [3] RP FUNCTION. RX PubMed=12169672; DOI=10.1073/pnas.182267299; RA Crambert G., Fuzesi M., Garty H., Karlish S., Geering K.; RT "Phospholemman (FXYD1) associates with Na,K-ATPase and regulates its RT transport properties."; RL Proc. Natl. Acad. Sci. U.S.A. 99:11476-11481(2002). RN [4] RP INTERACTION WITH ATP1A1, AND PHOSPHORYLATION AT SER-83 AND SER-88. RX PubMed=16943195; DOI=10.1074/jbc.M606254200; RA Bossuyt J., Despa S., Martin J.L., Bers D.M.; RT "Phospholemman phosphorylation alters its fluorescence resonance RT energy transfer with the Na/K-ATPase pump."; RL J. Biol. Chem. 281:32765-32773(2006). RN [5] RP PHOSPHORYLATION AT SER-83; SER-88 AND THR-89, AND MUTAGENESIS OF RP SER-83; SER-88 AND THR-89. RX PubMed=19339511; DOI=10.1152/ajpcell.00523.2008; RA Fuller W., Howie J., McLatchie L.M., Weber R.J., Hastie C.J., RA Burness K., Pavlovic D., Shattock M.J.; RT "FXYD1 phosphorylation in vitro and in adult rat cardiac myocytes: RT threonine 69 is a novel substrate for protein kinase C."; RL Am. J. Physiol. 296:C1346-C1355(2009). RN [6] RP PHOSPHORYLATION, AND MUTAGENESIS OF SER-83 AND SER-88. RX PubMed=20861470; DOI=10.1152/ajpcell.00027.2010; RA Han F., Bossuyt J., Martin J.L., Despa S., Bers D.M.; RT "Role of phospholemman phosphorylation sites in mediating kinase- RT dependent regulation of the Na+-K+-ATPase."; RL Am. J. Physiol. 299:C1363-C1369(2010). RN [7] RP PHOSPHORYLATION AT SER-83 AND SER-88, AND MUTAGENESIS OF SER-83 AND RP SER-88. RX PubMed=21220422; DOI=10.1074/jbc.M110.198036; RA Song Q., Pallikkuth S., Bossuyt J., Bers D.M., Robia S.L.; RT "Phosphomimetic mutations enhance oligomerization of phospholemman and RT modulate its interaction with the Na/K-ATPase."; RL J. Biol. Chem. 286:9120-9126(2011). RN [8] RP FUNCTION, INTERACTION WITH ATP1A1 AND ATP1B1, GLUTATHIONYLATION AT RP CYS-62, AND MUTAGENESIS OF CYS-60; CYS-62 AND LYS-63. RX PubMed=21454534; DOI=10.1074/jbc.M110.184101; RA Bibert S., Liu C.C., Figtree G.A., Garcia A., Hamilton E.J., RA Marassi F.M., Sweadner K.J., Cornelius F., Geering K., Rasmussen H.H.; RT "FXYD proteins reverse inhibition of the Na+-K+ pump mediated by RT glutathionylation of its beta1 subunit."; RL J. Biol. Chem. 286:18562-18572(2011). 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 (PubMed:12169672). Inhibits CC NKA activity in its unphosphorylated state and stimulates activity CC when phosphorylated (By similarity). Reduces glutathionylation of CC the NKA beta-1 subunit ATP1B1, thus reversing glutathionylation- CC mediated inhibition of ATP1B1 (PubMed:21454534). Contributes to CC female sexual development by maintaining the excitability of CC neurons which secrete gonadotropin-releasing hormone (By CC similarity). {ECO:0000250|UniProtKB:O08589, CC ECO:0000250|UniProtKB:Q9Z239, ECO:0000269|PubMed:12169672, CC ECO:0000269|PubMed:21454534}. CC -!- SUBUNIT: Homotetramer (By similarity). Monomer (By similarity). CC Regulatory subunit of the sodium/potassium-transporting ATPase CC (NKA) which is composed of a catalytic alpha subunit, a 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 CC catalytic alpha-1 subunit ATP1A1 (PubMed:16943195, CC PubMed:21454534). Also interacts with the catalytic alpha-2 and CC alpha-3 subunits ATP1A2 and ATP1A3 (By similarity). Very little CC interaction with the alpha subunits ATP1A1, ATP1A2 or ATP1A3 when CC phosphorylated at Ser-83 (By similarity). Interacts with non- CC catalytic beta-1 subunit ATP1B1 (PubMed:21454534). Oxidative CC stress decreases interaction with ATP1A1 but increases interaction CC with ATP1B1 (PubMed:21454534). {ECO:0000250|UniProtKB:O00168, CC ECO:0000250|UniProtKB:O08589, ECO:0000250|UniProtKB:Q3SZX0, CC ECO:0000250|UniProtKB:Q9Z239, ECO:0000269|PubMed:16943195, CC ECO:0000269|PubMed:21454534}. CC -!- SUBCELLULAR LOCATION: Cell membrane, sarcolemma CC {ECO:0000269|PubMed:1710217, ECO:0000269|PubMed:9486665}; Single- CC pass type I membrane 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: Present in heart, esophagus, stomach, aorta, CC skeletal muscle, smooth muscle, and liver but absent from brain CC and kidney. {ECO:0000269|PubMed:1710217}. 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 (PubMed:1710217, PubMed:20861470). Phosphorylated in CC response to insulin and adrenergic stimulation (By similarity). CC Phosphorylation at Ser-88 stimulates sodium/potassium-transporting CC ATPase activity while the unphosphorylated form inhibits CC sodium/potassium-transporting ATPase activity (By similarity). CC Phosphorylation increases tetramerization, decreases binding to CC ATP1A1 and reduces inhibition of ATP1A1 activity CC (PubMed:21220422). Phosphorylation at Ser-83 leads to greatly CC reduced interaction with ATP1A1, ATP1A2 and ATP1A3 (By CC similarity). May be phosphorylated by DMPK (By similarity). CC {ECO:0000250|UniProtKB:O00168, ECO:0000250|UniProtKB:O08589, CC ECO:0000269|PubMed:1710217, ECO:0000269|PubMed:20861470, CC ECO:0000269|PubMed:21220422}. CC -!- PTM: Palmitoylation increases half-life and stability and is CC enhanced upon phosphorylation at Ser-88 by PKA. CC {ECO:0000250|UniProtKB:O00168}. 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; M63934; -; NOT_ANNOTATED_CDS; mRNA. DR PIR; A40533; A40533. DR SMR; P56513; -. DR STRING; 9612.ENSCAFP00000010530; -. DR TCDB; 1.A.27.1.1; the phospholemman (plm) family. DR iPTMnet; P56513; -. DR PaxDb; P56513; -. DR eggNOG; ENOG410J08K; Eukaryota. DR eggNOG; ENOG410YYN6; LUCA. DR HOGENOM; HOG000234467; -. DR InParanoid; P56513; -. DR Proteomes; UP000002254; Unplaced. 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:0042383; C:sarcolemma; IDA: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:0099106; F:ion channel regulator activity; IEA:InterPro. DR GO; GO:0017080; F:sodium channel regulator activity; IDA:UniProtKB. DR GO; GO:0010734; P:negative regulation of protein glutathionylation; IDA: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:2000649; P:regulation of sodium ion transmembrane transporter activity; IBA:GO_Central. DR GO; GO:1903406; P:regulation of sodium:potassium-exchanging ATPase activity; IDA:UniProtKB. 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 Cell membrane; Complete proteome; Direct protein sequencing; KW Glutathionylation; Ion transport; Lipoprotein; Membrane; Palmitate; KW Phosphoprotein; Potassium; Potassium transport; Reference proteome; KW Signal; Sodium; Sodium transport; Sodium/potassium transport; KW Transmembrane; Transmembrane helix; Transport. FT SIGNAL 1 20 {ECO:0000269|PubMed:1710217}. FT CHAIN 21 92 Phospholemman. FT /FTId=PRO_0000010358. 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:0000269|PubMed:21454534}. 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:0000269|PubMed:16943195, FT ECO:0000269|PubMed:19339511, FT ECO:0000269|PubMed:21220422}. FT MOD_RES 88 88 Phosphoserine; by PKA and PKC. FT {ECO:0000269|PubMed:16943195, FT ECO:0000269|PubMed:19339511, FT ECO:0000269|PubMed:21220422}. FT MOD_RES 89 89 Phosphothreonine; by PKC. FT {ECO:0000269|PubMed:19339511}. FT LIPID 60 60 S-palmitoyl cysteine. FT {ECO:0000250|UniProtKB:O00168}. FT LIPID 62 62 S-palmitoyl cysteine; alternate. FT {ECO:0000250|UniProtKB:O00168}. FT MUTAGEN 60 60 C->A: Does not affect glutathionylation. FT {ECO:0000269|PubMed:21454534}. FT MUTAGEN 62 62 C->A: Loss of glutathionylation and loss FT of ability to reduce glutathionylation of FT ATP1B1. {ECO:0000269|PubMed:21454534}. FT MUTAGEN 63 63 K->G: Loss of glutathionylation and loss FT of ability to reduce glutathionylation of FT ATP1B1. {ECO:0000269|PubMed:21454534}. FT MUTAGEN 83 83 S->A: Loss of phosphorylation. Decreased FT affinity of the sodium/potassium- FT transporting ATPase for Na(+). FT {ECO:0000269|PubMed:19339511, FT ECO:0000269|PubMed:20861470}. FT MUTAGEN 83 83 S->E: Phosphomimetic mutant which reduces FT binding to ATP1A1 and increases FXYD1 FT oligomerization. FT {ECO:0000269|PubMed:21220422}. FT MUTAGEN 88 88 S->A: Loss of phosphorylation. Decreased FT affinity of the sodium/potassium- FT transporting ATPase for Na(+). FT {ECO:0000269|PubMed:19339511, FT ECO:0000269|PubMed:20861470}. FT MUTAGEN 88 88 S->E: Phosphomimetic mutant which reduces FT binding to ATP1A1 and increases FXYD1 FT oligomerization. FT {ECO:0000269|PubMed:21220422}. FT MUTAGEN 89 89 T->A: Loss of phosphorylation. FT {ECO:0000269|PubMed:19339511}. SQ SEQUENCE 92 AA; 10500 MW; 890DE301BF8E740A CRC64; MAPLHHILVL CVGFLTTATA EAPQEHDPFT YDYQSLRIGG LIIAGILFIL GILIVLSRRC RCKFNQQQRT GEPDEEEGTF RSSIRRLSTR RR //