PLM_HUMAN
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 03-AUG-2022, entry version 172.
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}.
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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 PDB; 2JO1; NMR; -; A=21-92.
DR PDBsum; 2JO1; -.
DR AlphaFoldDB; O00168; -.
DR BMRB; O00168; -.
DR SMR; O00168; -.
DR BioGRID; 111363; 29.
DR IntAct; O00168; 10.
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 jPOST; O00168; -.
DR MassIVE; O00168; -.
DR MaxQB; O00168; -.
DR PaxDb; O00168; -.
DR PeptideAtlas; O00168; -.
DR PRIDE; O00168; -.
DR ProteomicsDB; 47759; -.
DR Antibodypedia; 65378; 304 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 CTD; 5348; -.
DR DisGeNET; 5348; -.
DR GeneCards; FXYD1; -.
DR HGNC; HGNC:4025; FXYD1.
DR HPA; ENSG00000266964; Tissue enhanced (skeletal muscle, tongue).
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; FTMANAE; -.
DR OrthoDB; 1621616at2759; -.
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 1068 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 94 other tissues.
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: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 InterPro; IPR000272; Ion-transport_regulator_FXYD.
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 Reference proteome; Signal; Sodium; Sodium transport;
KW Sodium/potassium transport; Transmembrane; 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 68..84
FT /note="Basic and acidic 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
