EPM2A_MOUSE
ID EPM2A_MOUSE Reviewed; 330 AA.
AC Q9WUA5; G5E8E2; Q8BY80;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 2.
DT 03-AUG-2022, entry version 157.
DE RecName: Full=Laforin {ECO:0000303|PubMed:16971387};
DE EC=3.1.3.- {ECO:0000269|PubMed:16971387, ECO:0000269|PubMed:18040046, ECO:0000269|PubMed:24430976};
DE EC=3.1.3.16;
DE EC=3.1.3.48 {ECO:0000269|PubMed:16971387};
DE AltName: Full=Glucan phosphatase;
DE AltName: Full=Lafora PTPase;
DE Short=LAFPTPase;
GN Name=Epm2a;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=ICR; TISSUE=Brain;
RX PubMed=10092504; DOI=10.1006/bbrc.1999.0402;
RA Ganesh S., Amano K., Delgado-Escueta A.V., Yamakawa K.;
RT "Isolation and characterization of mouse homologue for the human epilepsy
RT gene, EPM2A.";
RL Biochem. Biophys. Res. Commun. 257:24-28(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 10-137.
RC STRAIN=C57BL/6J; TISSUE=Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP DEVELOPMENTAL STAGE.
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).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=12019206; DOI=10.1093/hmg/11.11.1251;
RA Ganesh S., Delgado-Escueta A.V., Sakamoto T., Avila M.R., Machado-Salas J.,
RA Hoshii Y., Akagi T., Gomi H., Suzuki T., Amano K., Agarwala K.L.,
RA Hasegawa Y., Bai D.S., Ishihara T., Hashikawa T., Itohara S.,
RA Cornford E.M., Niki H., Yamakawa K.;
RT "Targeted disruption of the Epm2a gene causes formation of Lafora inclusion
RT bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired
RT behavioral response in mice.";
RL Hum. Mol. Genet. 11:1251-1262(2002).
RN [7]
RP SUBUNIT, CATALYTIC ACTIVITY, MUTAGENESIS OF TRP-32; PHE-83; ARG-107;
RP THR-193; CYS-265; GLN-292; TYR-293 AND PRO-300, AND ACTIVE SITE.
RX PubMed=16971387; DOI=10.1074/jbc.m607778200;
RA Liu Y., Wang Y., Wu C., Liu Y., Zheng P.;
RT "Dimerization of Laforin is required for its optimal phosphatase activity,
RT regulation of GSK3beta phosphorylation, and Wnt signaling.";
RL J. Biol. Chem. 281:34768-34774(2006).
RN [8]
RP FUNCTION AS A GLUCAN PHOSPHATASE, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE,
RP ACTIVE SITE, AND MUTAGENESIS OF TRP-32 AND CYS-265.
RX PubMed=18040046; DOI=10.1073/pnas.0707952104;
RA Tagliabracci V.S., Turnbull J., Wang W., Girard J.M., Zhao X., Skurat A.V.,
RA Delgado-Escueta A.V., Minassian B.A., Depaoli-Roach A.A., Roach P.J.;
RT "Laforin is a glycogen phosphatase, deficiency of which leads to elevated
RT phosphorylation of glycogen in vivo.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:19262-19266(2007).
RN [9]
RP FUNCTION IN GLYCOGEN METABOLISM, AND DISRUPTION PHENOTYPE.
RX PubMed=18852261; DOI=10.1074/jbc.m807428200;
RA Tagliabracci V.S., Girard J.M., Segvich D., Meyer C., Turnbull J., Zhao X.,
RA Minassian B.A., Depaoli-Roach A.A., Roach P.J.;
RT "Abnormal metabolism of glycogen phosphate as a cause for Lafora disease.";
RL J. Biol. Chem. 283:33816-33825(2008).
RN [10]
RP FUNCTION, AND COMPLEX FORMATION WITH NHLRC1 AND HSP70.
RX PubMed=19036738; DOI=10.1093/hmg/ddn398;
RA Garyali P., Siwach P., Singh P.K., Puri R., Mittal S., Sengupta S.,
RA Parihar R., Ganesh S.;
RT "The malin-laforin complex suppresses the cellular toxicity of misfolded
RT proteins by promoting their degradation through the ubiquitin-proteasome
RT system.";
RL Hum. Mol. Genet. 18:688-700(2009).
RN [11]
RP FUNCTION, INTERACTION WITH MAPT, AND DISRUPTION PHENOTYPE.
RX PubMed=19542233; DOI=10.1074/jbc.m109.009688;
RA Puri R., Suzuki T., Yamakawa K., Ganesh S.;
RT "Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an
RT animal model for Lafora disease.";
RL J. Biol. Chem. 284:22657-22663(2009).
RN [12]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=20453062; DOI=10.1093/hmg/ddq190;
RA Aguado C., Sarkar S., Korolchuk V.I., Criado O., Vernia S., Boya P.,
RA Sanz P., de Cordoba S.R., Knecht E., Rubinsztein D.C.;
RT "Laforin, the most common protein mutated in Lafora disease, regulates
RT autophagy.";
RL Hum. Mol. Genet. 19:2867-2876(2010).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22669944; DOI=10.1074/jbc.m111.331611;
RA Tiberia E., Turnbull J., Wang T., Ruggieri A., Zhao X.C., Pencea N.,
RA Israelian J., Wang Y., Ackerley C.A., Wang P., Liu Y., Minassian B.A.;
RT "Increased laforin and laforin binding to glycogen underlie Lafora body
RT formation in malin-deficient Lafora disease.";
RL J. Biol. Chem. 287:25650-25659(2012).
RN [14]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=23663739; DOI=10.1016/j.cmet.2013.04.006;
RA Nitschke F., Wang P., Schmieder P., Girard J.M., Awrey D.E., Wang T.,
RA Israelian J., Zhao X., Turnbull J., Heydenreich M., Kleinpeter E.,
RA Steup M., Minassian B.A.;
RT "Hyperphosphorylation of glucosyl C6 carbons and altered structure of
RT glycogen in the neurodegenerative epilepsy Lafora disease.";
RL Cell Metab. 17:756-767(2013).
RN [15]
RP INTERACTION WITH PPP1R3D.
RX PubMed=23624058; DOI=10.1016/j.biocel.2013.04.019;
RA Rubio-Villena C., Garcia-Gimeno M.A., Sanz P.;
RT "Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is
RT modulated by the laforin-malin complex.";
RL Int. J. Biochem. Cell Biol. 45:1479-1488(2013).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-265, AND TISSUE
RP SPECIFICITY.
RX PubMed=24430976; DOI=10.1093/brain/awt353;
RA Gayarre J., Duran-Trio L., Criado Garcia O., Aguado C., Juana-Lopez L.,
RA Crespo I., Knecht E., Bovolenta P., Rodriguez de Cordoba S.;
RT "The phosphatase activity of laforin is dispensable to rescue Epm2a-/-mice
RT from Lafora disease.";
RL Brain 137:806-818(2014).
RN [17]
RP FUNCTION.
RX PubMed=24068615; DOI=10.1007/s12035-013-8546-z;
RA Liu Y., Zeng L., Ma K., Baba O., Zheng P., Liu Y., Wang Y.;
RT "Laforin-malin complex degrades polyglucosan bodies in concert with
RT glycogen debranching enzyme and brain isoform glycogen phosphorylase.";
RL Mol. Neurobiol. 49:645-657(2014).
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 (PubMed:18040046, PubMed:18852261,
CC PubMed:19036738, PubMed:23663739, PubMed:24430976, PubMed:24068615).
CC Dephosphorylates phosphotyrosine and synthetic substrates, such as
CC para-nitrophenylphosphate (pNPP), and has low activity with
CC phosphoserine and phosphothreonine substrates (in vitro)
CC (PubMed:16971387, PubMed:24430976). Has also been shown to
CC dephosphorylate MAPT (PubMed:19542233). Shows strong phosphatase
CC activity towards complex carbohydrates in vitro, avoiding glycogen
CC hyperphosphorylation which is associated with reduced branching and
CC formation of insoluble aggregates (PubMed:18040046, PubMed:18852261,
CC PubMed:23663739). Forms a complex with NHLRC1/malin and HSP70, which
CC suppresses the cellular toxicity of misfolded proteins by promoting
CC their degradation through the ubiquitin-proteasome system (UPS)
CC (PubMed:19036738, PubMed:24068615). 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 (PubMed:20453062). {ECO:0000269|PubMed:16971387,
CC ECO:0000269|PubMed:18040046, ECO:0000269|PubMed:18852261,
CC ECO:0000269|PubMed:19036738, ECO:0000269|PubMed:19542233,
CC ECO:0000269|PubMed:20453062, ECO:0000269|PubMed:22669944,
CC ECO:0000269|PubMed:23663739, ECO:0000269|PubMed:24068615,
CC ECO:0000269|PubMed:24430976}.
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, ECO:0000269|PubMed:16971387};
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 (PubMed:16971387). Interacts with PPP1R3B, PPP1R3C,
CC HIRIP5, and EPM2AIP1 (By similarity). Binds glycogen and Lafora bodies.
CC Interacts with NHLRC1/malin (via the NHL repeats) (By similarity).
CC Forms a complex with NHLRC1/malin and HSP70 (PubMed:19036738).
CC Interacts with PPP1R3D; in the presence of NHLC1/malin the interaction
CC leads to ubiquitination and autophagic degradation of PPP1R3D
CC (PubMed:23624058). Interacts (via the phosphatase domain) with
CC MAPT/Tau; the interaction dephosphorylates MAPT (PubMed:19542233).
CC Interacts with PRDM8 (By similarity). {ECO:0000250|UniProtKB:O95278,
CC ECO:0000269|PubMed:16971387, ECO:0000269|PubMed:19036738,
CC ECO:0000269|PubMed:19542233, ECO:0000269|PubMed:23624058}.
CC -!- INTERACTION:
CC Q9WUA5; Q9WV60: Gsk3b; NbExp=2; IntAct=EBI-1040928, EBI-400793;
CC Q9WUA5; Q6VVB1: NHLRC1; Xeno; NbExp=12; IntAct=EBI-1040928, EBI-6426628;
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: Detected in skeletal muscle and in brain (at
CC protein level) (PubMed:24430976). Widely expressed. Higher levels of
CC expression are found in heart, brain, liver, skeletal muscle and kidney
CC (PubMed:10092504). {ECO:0000269|PubMed:10092504,
CC ECO:0000269|PubMed:24430976}.
CC -!- DEVELOPMENTAL STAGE: In the embryo, highly expressed at 17 dpc.
CC Detected in all postnatal stages, but highest expression is found at
CC day 160 after birth. {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 -!- DISRUPTION PHENOTYPE: Impaired behavioral responses, ataxia,
CC spontaneous myoclonic seizures and progressive accumulation of poorly-
CC branched, insoluble forms of glycogen (Lafora bodies) in liver, brain
CC and skeletal muscle tissue (PubMed:12019206, PubMed:18040046,
CC PubMed:24430976). Expression of both wild-type Epm2a and mutated Epm2a
CC without phosphatase activity can abolish the appearance of Lafora
CC bodies in brain and heart from 7 to over 12 month old mutant mice
CC (PubMed:24430976). At 3 months of age, overall glycogen levels are
CC normal; by 9 months of age, a 3-fold increase in overall glycogen
CC levels and a 6-fold increase in glycogen phosphate levels is observed
CC (PubMed:18040046, PubMed:18852261, PubMed:22669944, PubMed:23663739).
CC Muscle glycogen has an altered structure, with a reduced size, an
CC abnormally high proportion of very short side chains, fewer medium-
CC length chains and an increased number of long chains (PubMed:23663739).
CC Glycogen synthase (Gys1) and 1,4-alpha-glucan-branching enzyme (Gbe1)
CC activities in brain and muscle tissue are normal (PubMed:18040046). 10
CC month old mice have neurofibrillary tangles (NFTs, aggregates of
CC hyperphosphorylated Mapt/Tau) in brain and muscle tissue, however NFTs
CC are not observed in 4 and 6 month old mice (PubMed:19542233). 3- and
CC 12- month old mice show reduced numbers of autophagosomes in liver
CC extracts, and 3-month old starved mice have increased levels of the
CC autophagy dysfunction marker Map1lc3b/LC3-II and increased levels of
CC ubiquitinated proteins, suggesting impaired macroautophagy
CC (PubMed:20453062). {ECO:0000269|PubMed:12019206,
CC ECO:0000269|PubMed:18040046, ECO:0000269|PubMed:18852261,
CC ECO:0000269|PubMed:19542233, ECO:0000269|PubMed:20453062,
CC ECO:0000269|PubMed:22669944, ECO:0000269|PubMed:23663739,
CC ECO:0000269|PubMed:24430976}.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC {ECO:0000305}.
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DR EMBL; AF124044; AAD26336.1; -; mRNA.
DR EMBL; AC101984; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC157018; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466562; EDL03516.1; -; Genomic_DNA.
DR EMBL; AK041609; BAC31004.1; -; mRNA.
DR CCDS; CCDS23698.1; -.
DR RefSeq; NP_034276.2; NM_010146.2.
DR AlphaFoldDB; Q9WUA5; -.
DR SMR; Q9WUA5; -.
DR BioGRID; 199484; 3.
DR IntAct; Q9WUA5; 3.
DR MINT; Q9WUA5; -.
DR STRING; 10090.ENSMUSP00000066050; -.
DR CAZy; CBM20; Carbohydrate-Binding Module Family 20.
DR PhosphoSitePlus; Q9WUA5; -.
DR PaxDb; Q9WUA5; -.
DR PRIDE; Q9WUA5; -.
DR ProteomicsDB; 275632; -.
DR Antibodypedia; 19839; 527 antibodies from 38 providers.
DR DNASU; 13853; -.
DR Ensembl; ENSMUST00000069106; ENSMUSP00000066050; ENSMUSG00000055493.
DR GeneID; 13853; -.
DR KEGG; mmu:13853; -.
DR UCSC; uc007ejv.1; mouse.
DR CTD; 7957; -.
DR MGI; MGI:1341085; Epm2a.
DR VEuPathDB; HostDB:ENSMUSG00000055493; -.
DR eggNOG; KOG1716; Eukaryota.
DR GeneTree; ENSGT00390000010101; -.
DR HOGENOM; CLU_076792_0_0_1; -.
DR InParanoid; Q9WUA5; -.
DR OMA; HLYKDCG; -.
DR OrthoDB; 865142at2759; -.
DR PhylomeDB; Q9WUA5; -.
DR TreeFam; TF332841; -.
DR BioGRID-ORCS; 13853; 6 hits in 71 CRISPR screens.
DR ChiTaRS; Epm2a; mouse.
DR PRO; PR:Q9WUA5; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q9WUA5; protein.
DR Bgee; ENSMUSG00000055493; Expressed in hindlimb stylopod muscle and 81 other tissues.
DR Genevisible; Q9WUA5; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0098554; C:cytoplasmic side of endoplasmic reticulum membrane; IDA:MGI.
DR GO; GO:0098556; C:cytoplasmic side of rough endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IMP:MGI.
DR GO; GO:0030425; C:dendrite; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0043204; C:perikaryon; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005844; C:polysome; ISO:MGI.
DR GO; GO:0030246; F:carbohydrate binding; ISS:UniProtKB.
DR GO; GO:0019203; F:carbohydrate phosphatase activity; IDA:MGI.
DR GO; GO:0004373; F:glycogen (starch) synthase activity; IEP:MGI.
DR GO; GO:2001069; F:glycogen binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:MGI.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0016791; F:phosphatase activity; IDA:MGI.
DR GO; GO:0004721; F:phosphoprotein phosphatase activity; IDA:MGI.
DR GO; GO:0030247; F:polysaccharide binding; IDA:MGI.
DR GO; GO:0046983; F:protein dimerization activity; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IDA:MGI.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IDA:MGI.
DR GO; GO:0008138; F:protein tyrosine/serine/threonine phosphatase activity; TAS:MGI.
DR GO; GO:2001070; F:starch binding; IDA:MGI.
DR GO; GO:0000045; P:autophagosome assembly; IMP:MGI.
DR GO; GO:0006914; P:autophagy; IMP:MGI.
DR GO; GO:0006816; P:calcium ion transport; IMP:MGI.
DR GO; GO:0046835; P:carbohydrate phosphorylation; IMP:MGI.
DR GO; GO:0044260; P:cellular macromolecule metabolic process; IMP:MGI.
DR GO; GO:0016311; P:dephosphorylation; ISO:MGI.
DR GO; GO:0014009; P:glial cell proliferation; IGI:MGI.
DR GO; GO:0005978; P:glycogen biosynthetic process; IDA:MGI.
DR GO; GO:0005977; P:glycogen metabolic process; IMP:MGI.
DR GO; GO:0046959; P:habituation; IMP:MGI.
DR GO; GO:0015813; P:L-glutamate transmembrane transport; IMP:MGI.
DR GO; GO:0007005; P:mitochondrion organization; IMP:MGI.
DR GO; GO:0045786; P:negative regulation of cell cycle; IMP:MGI.
DR GO; GO:0035305; P:negative regulation of dephosphorylation; ISO:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:MGI.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; IMP:MGI.
DR GO; GO:0010923; P:negative regulation of phosphatase activity; ISO:MGI.
DR GO; GO:0032007; P:negative regulation of TOR signaling; ISO:MGI.
DR GO; GO:0007399; P:nervous system development; IMP:MGI.
DR GO; GO:0035335; P:peptidyl-tyrosine dephosphorylation; ISO:MGI.
DR GO; GO:0046838; P:phosphorylated carbohydrate dephosphorylation; ISS:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IMP:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:MGI.
DR GO; GO:0006470; P:protein dephosphorylation; ISO:MGI.
DR GO; GO:0001558; P:regulation of cell growth; IMP:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:2000465; P:regulation of glycogen (starch) synthase activity; IMP:MGI.
DR GO; GO:0042325; P:regulation of phosphorylation; IMP:MGI.
DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IMP:MGI.
DR GO; GO:0042306; P:regulation of protein import into nucleus; IDA:MGI.
DR GO; GO:0045859; P:regulation of protein kinase activity; IMP:MGI.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; IGI:MGI.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IMP:MGI.
DR GO; GO:0031396; P:regulation of protein ubiquitination; IGI:MGI.
DR GO; GO:1904666; P:regulation of ubiquitin protein ligase activity; IMP:MGI.
DR GO; GO:0016055; P:Wnt signaling pathway; IMP:MGI.
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 1: Evidence at protein 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..330
FT /note="Laforin"
FT /id="PRO_0000094839"
FT DOMAIN 1..123
FT /note="CBM20"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00594"
FT DOMAIN 155..322
FT /note="Tyrosine-protein phosphatase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160"
FT MOTIF 265..271
FT /note="Glucan phosphatase signature motif CXAGXGR"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT ACT_SITE 265
FT /note="Phosphocysteine intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160,
FT ECO:0000269|PubMed:16971387, ECO:0000269|PubMed:18040046"
FT BINDING 32
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 86
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 102..106
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 196
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 234
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 240
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 266..271
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 303
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT SITE 328
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 MUTAGEN 32
FT /note="W->G: Loss of glycogen phosphatase activity. Nearly
FT abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:16971387,
FT ECO:0000269|PubMed:18040046"
FT MUTAGEN 83
FT /note="F->L: Abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:16971387"
FT MUTAGEN 107
FT /note="R->C: Abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:16971387"
FT MUTAGEN 193
FT /note="T->I: Nearly abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:16971387"
FT MUTAGEN 265
FT /note="C->S: Loss of phosphatase activity with glycogen and
FT synthetic substrates."
FT /evidence="ECO:0000269|PubMed:16971387,
FT ECO:0000269|PubMed:18040046, ECO:0000269|PubMed:24430976"
FT MUTAGEN 292
FT /note="Q->L: Abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:16971387"
FT MUTAGEN 293
FT /note="Y->N: Nearly abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:16971387"
FT MUTAGEN 300
FT /note="P->L: Abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:16971387"
FT CONFLICT 140
FT /note="H -> R (in Ref. 1; AAD26336)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 330 AA; 36958 MW; 89B18C64BBBAB02A CRC64;
MLFRFGVVVP PAVAGARQEL LLAGSRPELG RWEPHGAVRL RPAGTAAGAA ALALQEPGLW
LAEVELEAYE EAGGAEPGRV DTFWYKFLQR EPGGELHWEG NGPHHDRCCT YNEDNLVDGV
YCLPVGHWIE ATGHTNEMKH TTDFYFNIAG HQAMHYSRIL PNIWLGSCPR QLEHVTIKLK
HELGVTAVMN FQTEWDIIQN SSGCNRYPEP MTPDTMMKLY KEEGLSYIWM PTPDMSTEGR
VQMLPQAVCL LHALLENGHT VYVHCNAGVG RSTAAVCGWL HYVIGWNLRK VQYFIMAKRP
AVYIDEDALA QAQQDFSQKF GKVHSSICAL
