EPM2A_RAT
ID EPM2A_RAT Reviewed; 331 AA.
AC Q91XQ2; F1LPW7;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 2.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Laforin;
DE EC=3.1.3.- {ECO:0000250|UniProtKB:Q9WUA5};
DE EC=3.1.3.16;
DE EC=3.1.3.48 {ECO:0000250|UniProtKB:O95278};
DE AltName: Full=Glucan phosphatase;
DE AltName: Full=Lafora PTPase;
DE Short=LAFPTPase;
GN Name=Epm2a;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 5-331, AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley; TISSUE=Brain cortex;
RX PubMed=11355878; DOI=10.1006/bbrc.2001.4914;
RA Ganesh S., Agarwala K.L., Amano K., Suzuki T., Delgado-Escueta A.V.,
RA Yamakawa K.;
RT "Regional and developmental expression of Epm2a gene and its evolutionary
RT conservation.";
RL Biochem. Biophys. Res. Commun. 283:1046-1053(2001).
CC -!- FUNCTION: Plays an important role in preventing glycogen
CC hyperphosphorylation and the formation of insoluble aggregates, via its
CC activity as glycogen phosphatase, and by promoting the ubiquitination
CC of proteins involved in glycogen metabolism via its interaction with
CC the E3 ubiquitin ligase NHLRC1/malin. Dephosphorylates phosphotyrosine
CC and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and
CC has low activity with phosphoserine and phosphothreonine substrates (in
CC vitro). Has also been shown to dephosphorylate MAPT. Shows strong
CC phosphatase activity towards complex carbohydrates in vitro, avoiding
CC glycogen hyperphosphorylation which is associated with reduced
CC branching and formation of insoluble aggregates. Forms a complex with
CC NHLRC1/malin and HSP70, which suppresses the cellular toxicity of
CC misfolded proteins by promoting their degradation through the
CC ubiquitin-proteasome system (UPS). Acts as a scaffold protein to
CC facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes
CC proteasome-independent protein degradation through the macroautophagy
CC pathway. {ECO:0000250|UniProtKB:O95278, ECO:0000250|UniProtKB:Q9WUA5}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620; EC=3.1.3.48; Evidence={ECO:0000255|PROSITE-
CC ProRule:PRU10044};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] +
CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:83421; EC=3.1.3.16;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:61977; EC=3.1.3.16;
CC -!- SUBUNIT: Homodimer. Interacts with itself. Interacts with PPP1R3B,
CC PPP1R3C, PPP1R3D, HIRIP5, and EPM2AIP1. Binds glycogen and Lafora
CC bodies. Interacts with NHLRC1/malin (via the NHL repeats). Forms a
CC complex with NHLRC1/malin and HSP70. Interacts with PPP1R3D; in the
CC presence of NHLC1/malin the interaction leads to ubiquitination and
CC autophagic degradation of PPP1R3D. Interacts (via the phosphatase
CC domain) with MAPT/Tau; the interaction dephosphorylates MAPT. Interacts
CC with PRDM8. {ECO:0000250|UniProtKB:O95278}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O95278}.
CC Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O95278};
CC Peripheral membrane protein {ECO:0000250|UniProtKB:O95278}; Cytoplasmic
CC side {ECO:0000250|UniProtKB:O95278}. Cell membrane
CC {ECO:0000250|UniProtKB:O95278}. Note=Colocalizes with glycogen synthase
CC in punctate structures in the cytoplasm. Primarily associated with
CC polyribosomes at the rough endoplasmic reticulum, and also detected at
CC the plasma membrane. Under glycogenolytic conditions localizes to the
CC nucleus. {ECO:0000250|UniProtKB:O95278}.
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:11355878}.
CC -!- DOMAIN: The CBM20 domain mediates binding to cytoplasmic glycogen and
CC to Lafora polyglucosan bodies. {ECO:0000250|UniProtKB:O95278}.
CC -!- PTM: Polyubiquitinated by NHLRC1/malin. {ECO:0000250|UniProtKB:O95278}.
CC -!- PTM: Phosphorylation on Ser-25 by AMPK affects the phosphatase activity
CC of the enzyme and its ability to homodimerize and interact with NHLRC1,
CC PPP1R3C or PRKAA2. {ECO:0000250|UniProtKB:O95278}.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC {ECO:0000305}.
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DR EMBL; AABR06000316; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000317; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000318; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000319; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000320; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000321; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000322; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000323; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000324; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000325; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000326; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000327; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06000328; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH473994; EDL93717.1; -; Genomic_DNA.
DR EMBL; AF347030; AAK60619.1; -; mRNA.
DR RefSeq; NP_001263691.1; NM_001276762.1.
DR AlphaFoldDB; Q91XQ2; -.
DR SMR; Q91XQ2; -.
DR BioGRID; 250254; 1.
DR STRING; 10116.ENSRNOP00000058646; -.
DR PaxDb; Q91XQ2; -.
DR PeptideAtlas; Q91XQ2; -.
DR Ensembl; ENSRNOT00000099572; ENSRNOP00000076978; ENSRNOG00000040242.
DR GeneID; 114005; -.
DR KEGG; rno:114005; -.
DR CTD; 7957; -.
DR RGD; 71047; Epm2a.
DR eggNOG; KOG1716; Eukaryota.
DR GeneTree; ENSGT00390000010101; -.
DR HOGENOM; CLU_076792_0_0_1; -.
DR InParanoid; Q91XQ2; -.
DR OMA; HLYKDCG; -.
DR OrthoDB; 865142at2759; -.
DR TreeFam; TF332841; -.
DR PRO; PR:Q91XQ2; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Proteomes; UP000234681; Chromosome 1.
DR Bgee; ENSRNOG00000040242; Expressed in quadriceps femoris and 17 other tissues.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0098554; C:cytoplasmic side of endoplasmic reticulum membrane; ISO:RGD.
DR GO; GO:0098556; C:cytoplasmic side of rough endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0030425; C:dendrite; ISO:RGD.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0043204; C:perikaryon; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005844; C:polysome; IEA:Ensembl.
DR GO; GO:0030246; F:carbohydrate binding; ISS:UniProtKB.
DR GO; GO:0019203; F:carbohydrate phosphatase activity; ISS:UniProtKB.
DR GO; GO:0004373; F:glycogen (starch) synthase activity; ISO:RGD.
DR GO; GO:2001069; F:glycogen binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0016791; F:phosphatase activity; ISO:RGD.
DR GO; GO:0004721; F:phosphoprotein phosphatase activity; ISO:RGD.
DR GO; GO:0030247; F:polysaccharide binding; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; ISO:RGD.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; ISO:RGD.
DR GO; GO:0008138; F:protein tyrosine/serine/threonine phosphatase activity; IEA:InterPro.
DR GO; GO:2001070; F:starch binding; ISO:RGD.
DR GO; GO:0000045; P:autophagosome assembly; ISO:RGD.
DR GO; GO:0006914; P:autophagy; ISO:RGD.
DR GO; GO:0006816; P:calcium ion transport; ISO:RGD.
DR GO; GO:0046835; P:carbohydrate phosphorylation; ISO:RGD.
DR GO; GO:0044260; P:cellular macromolecule metabolic process; ISO:RGD.
DR GO; GO:0016311; P:dephosphorylation; ISS:UniProtKB.
DR GO; GO:0014009; P:glial cell proliferation; ISO:RGD.
DR GO; GO:0005978; P:glycogen biosynthetic process; ISO:RGD.
DR GO; GO:0005977; P:glycogen metabolic process; ISS:UniProtKB.
DR GO; GO:0046959; P:habituation; ISO:RGD.
DR GO; GO:0015813; P:L-glutamate transmembrane transport; ISO:RGD.
DR GO; GO:0007005; P:mitochondrion organization; ISO:RGD.
DR GO; GO:0045786; P:negative regulation of cell cycle; ISO:RGD.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; ISO:RGD.
DR GO; GO:0032007; P:negative regulation of TOR signaling; ISO:RGD.
DR GO; GO:0007399; P:nervous system development; ISO:RGD.
DR GO; GO:0035335; P:peptidyl-tyrosine dephosphorylation; ISO:RGD.
DR GO; GO:0046838; P:phosphorylated carbohydrate dephosphorylation; ISS:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; ISO:RGD.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISO:RGD.
DR GO; GO:0006470; P:protein dephosphorylation; ISO:RGD.
DR GO; GO:0001558; P:regulation of cell growth; ISO:RGD.
DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR GO; GO:2000465; P:regulation of glycogen (starch) synthase activity; ISO:RGD.
DR GO; GO:0042325; P:regulation of phosphorylation; ISO:RGD.
DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; ISO:RGD.
DR GO; GO:0042306; P:regulation of protein import into nucleus; ISO:RGD.
DR GO; GO:0045859; P:regulation of protein kinase activity; ISO:RGD.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; ISO:RGD.
DR GO; GO:0001932; P:regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0031396; P:regulation of protein ubiquitination; ISO:RGD.
DR GO; GO:1904666; P:regulation of ubiquitin protein ligase activity; ISO:RGD.
DR GO; GO:0016055; P:Wnt signaling pathway; ISO:RGD.
DR CDD; cd05806; CBM20_laforin; 1.
DR CDD; cd14526; DSP_laforin-like; 1.
DR Gene3D; 2.60.40.10; -; 1.
DR Gene3D; 3.90.190.10; -; 1.
DR InterPro; IPR013784; Carb-bd-like_fold.
DR InterPro; IPR034831; CBM20_laforin.
DR InterPro; IPR002044; CBM_fam20.
DR InterPro; IPR045204; DSP_laforin-like.
DR InterPro; IPR000340; Dual-sp_phosphatase_cat-dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR042942; Laforin.
DR InterPro; IPR029021; Prot-tyrosine_phosphatase-like.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR InterPro; IPR000387; Tyr_Pase_dom.
DR InterPro; IPR020422; TYR_PHOSPHATASE_DUAL_dom.
DR PANTHER; PTHR46864; PTHR46864; 1.
DR Pfam; PF00686; CBM_20; 1.
DR Pfam; PF00782; DSPc; 1.
DR SMART; SM01065; CBM_2; 1.
DR SMART; SM00195; DSPc; 1.
DR SUPFAM; SSF49452; SSF49452; 1.
DR SUPFAM; SSF52799; SSF52799; 1.
DR PROSITE; PS51166; CBM20; 1.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
DR PROSITE; PS50054; TYR_PHOSPHATASE_DUAL; 1.
PE 2: Evidence at transcript level;
KW Autophagy; Carbohydrate metabolism; Cell membrane; Cytoplasm;
KW Endoplasmic reticulum; Glycogen metabolism; Hydrolase; Membrane;
KW Phosphoprotein; Protein phosphatase; Reference proteome; Ubl conjugation.
FT CHAIN 1..331
FT /note="Laforin"
FT /id="PRO_0000094840"
FT DOMAIN 1..124
FT /note="CBM20"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00594"
FT DOMAIN 156..323
FT /note="Tyrosine-protein phosphatase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160"
FT MOTIF 266..272
FT /note="Glucan phosphatase signature motif CXAGXGR"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT ACT_SITE 266
FT /note="Phosphocysteine intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160"
FT BINDING 32
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 87
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 103..107
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 197
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 235
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 241
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 267..272
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 304
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT SITE 329
FT /note="Required for homodimerization"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT MOD_RES 25
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT CONFLICT 9..10
FT /note="VP -> DQ (in Ref. 3; AAK60619)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 331 AA; 37144 MW; C97D07AA55A534FC CRC64;
MLFRFGVVVP PAVAGTRLEL LLAGSRPELG RWEPRGAVRL RPAGTAAGAA ALALQEPGLW
LAEVELAPEE EAADGAEPGR IDTFWYKFLQ REPGGELHWE GNGPHHDRCC TYNENNLVDG
VYCLPVGHWI EATGHTNEMK HTTDFYFNIA GHQAMHYSRI LPNIWLGSCP RQLEHVTIKL
KHELGITAVM NFQTEWDIIQ NSSGCNRYPE PMTPDTMMKL YKEEGLAYIW MPTPDMSTEG
RVQMLPQAVC LLHALLENGH TVYVHCNAGV GRSTAAVCGW LHYVIGWSLR KVQYFIMAKR
PAVYIDEEAL AQAQQDFFQK FGKVHSSICT L
