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Q9WUA5

- EPM2A_MOUSE

UniProt

Q9WUA5 - EPM2A_MOUSE

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Protein

Laforin

Gene
Epm2a
Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

Has been shown to have both dual-specificity protein phosphatase and glucan phosphatase activities and, together with the E3 ubiquitin ligase NHLRC1/malin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. Dephosphorylates phosphotyrosine, phosphoserine and phosphothreonine substrates in vitro. Has also been shown to dephosphorylate MAPT. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.6 Publications

Catalytic activityi

Protein tyrosine phosphate + H2O = protein tyrosine + phosphate.
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei265 – 2651Phosphocysteine intermediate1 Publication
Sitei328 – 3281Required for homodimerization By similarity

GO - Molecular functioni

  1. phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity Source: RefGenome
  2. protein binding Source: IntAct
  3. protein tyrosine/serine/threonine phosphatase activity Source: RefGenome
  4. protein tyrosine phosphatase activity Source: MGI
  5. starch binding Source: InterPro

GO - Biological processi

  1. autophagy Source: UniProtKB-KW
  2. glycogen metabolic process Source: UniProtKB-KW
  3. habituation Source: MGI
  4. inositol phosphate dephosphorylation Source: RefGenome
  5. nervous system development Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protein phosphatase

Keywords - Biological processi

Autophagy, Carbohydrate metabolism, Glycogen metabolism

Enzyme and pathway databases

ReactomeiREACT_188939. Glycogen synthesis.
REACT_203841. Myoclonic epilepsy of Lafora.

Protein family/group databases

CAZyiCBM20. Carbohydrate-Binding Module Family 20.

Names & Taxonomyi

Protein namesi
Recommended name:
Laforin (EC:3.1.3.-, EC:3.1.3.16, EC:3.1.3.48)
Alternative name(s):
Glucan phosphatase
Lafora PTPase
Short name:
LAFPTPase
Gene namesi
Name:Epm2a
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 10

Organism-specific databases

MGIiMGI:1341085. Epm2a.

Subcellular locationi

Cytoplasm. Endoplasmic reticulum
Note: Under glycogenolytic conditions localizes to the nucleus By similarity.1 Publication

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. cytosol Source: MGI
  3. endoplasmic reticulum Source: UniProtKB-SubCell
  4. nucleus Source: MGI
  5. polysome Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum

Pathology & Biotechi

Disruption phenotypei

Impaired behavioral responses, ataxia, spontaneous myoclonic seizures and progressive accumulation of poorly-branched, insoluble forms of glycogen (Lafora bodies) in liver, brain and skeletal muscle tissue. At 3 months of age, overall glycogen levels are normal; by 9 months of age, a 3-fold increase in overall glycogen levels and a 6-fold increase in glycogen phosphate levels is observed. Glycogen synthase (Gys1) and 1,4-alpha-glucan-branching enzyme (Gbe1) activities in brain and muscle tissue are normal. 10 month old mice have neurofibrillary tangles (NFTs, aggregates of hyperphosphorylated Mapt/Tau) in brain and muscle tissue, however NFTs are not observed in 4 and 6 month old mice. 3- and 12- month old mice show reduced numbers of autophagosomes in liver extracts, and 3-month old starved mice have increased levels of the autophagy dysfunction marker Map1lc3b/LC3-II and increased levels of ubiquitinated proteins, suggesting impaired macroautophagy.5 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi32 – 321W → G: Loss of glycogen phosphatase activity. 1 Publication
Mutagenesisi265 – 2651C → S: Loss of glycogen phosphatase activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 330330LaforinPRO_0000094839Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei25 – 251Phosphoserine; by AMPK By similarity

Post-translational modificationi

Polyubiquitinated by NHLRC1/malin By similarity.
Phosphorylation on Ser-25 by AMPK affects the phosphatase activity of the enzyme and its ability to homodimerize and interact with NHLRC1, PPP1R3C or PRKAA2 By similarity.

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiQ9WUA5.

PTM databases

PhosphoSiteiQ9WUA5.

Expressioni

Tissue specificityi

Widely expressed. Higher levels of expression are found in heart, brain, liver, skeletal muscle and kidney. Found in neuronal dendrites and perikarya, but not in axons.2 Publications

Developmental stagei

In the embryo, highly expressed at 17 dpc. Detected in all postnatal stages, but highest expression is found at day 160 after birth.1 Publication

Gene expression databases

GenevestigatoriQ9WUA5.

Interactioni

Subunit structurei

Interacts with itself; however no biological function has been identified for the dimer. Interacts with PPP1R3B, PPP1R3C, HIRIP5, and EPM2AIP1. Binds glycogen and Lafora bodies. Interacts with NHLRC1/malin (via the NHL repeats) By similarity. Forms a complex with NHLRC1/malin and HSP70. Interacts with PPP1R3D; in the presence of NHLC1/malin the interaction leads to ubiquitination and autophagic degradation of PPP1R3D. Interacts (via the phosphatase domain) with MAPT/Tau; the interaction dephosphorylates MAPT.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Gsk3bQ9WV602EBI-1040928,EBI-400793
NHLRC1Q6VVB112EBI-1040928,EBI-6426628From a different organism.

Protein-protein interaction databases

IntActiQ9WUA5. 3 interactions.
MINTiMINT-8374088.

Structurei

3D structure databases

ProteinModelPortaliQ9WUA5.
SMRiQ9WUA5. Positions 8-108, 153-300.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1 – 123123CBM20Add
BLAST
Domaini242 – 31069Tyrosine-protein phosphataseAdd
BLAST

Sequence similaritiesi

Phylogenomic databases

eggNOGiNOG243912.
GeneTreeiENSGT00390000010101.
HOGENOMiHOG000285975.
HOVERGENiHBG051493.
InParanoidiQ9WUA5.
KOiK14165.
OMAiHWIEVSG.
OrthoDBiEOG7RJPRM.
TreeFamiTF332841.

Family and domain databases

Gene3Di2.60.40.10. 1 hit.
3.90.190.10. 1 hit.
InterProiIPR013784. Carb-bd-like_fold.
IPR002044. CBM_fam20.
IPR000340. Dual-sp_phosphatase_cat-dom.
IPR020422. Dual-sp_phosphatase_subgr_cat.
IPR024950. DUSP.
IPR013783. Ig-like_fold.
IPR029021. Prot-tyrosine_phosphatase-like.
IPR000387. Tyr/Dual-sp_Pase.
IPR016130. Tyr_Pase_AS.
[Graphical view]
PANTHERiPTHR10159. PTHR10159. 1 hit.
PfamiPF00686. CBM_20. 1 hit.
PF00782. DSPc. 1 hit.
[Graphical view]
SMARTiSM01065. CBM_2. 1 hit.
[Graphical view]
SUPFAMiSSF49452. SSF49452. 1 hit.
SSF52799. SSF52799. 1 hit.
PROSITEiPS51166. CBM20. 1 hit.
PS00383. TYR_PHOSPHATASE_1. 1 hit.
PS50056. TYR_PHOSPHATASE_2. 1 hit.
PS50054. TYR_PHOSPHATASE_DUAL. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9WUA5-1 [UniParc]FASTAAdd to Basket

« Hide

MLFRFGVVVP PAVAGARQEL LLAGSRPELG RWEPHGAVRL RPAGTAAGAA    50
ALALQEPGLW LAEVELEAYE EAGGAEPGRV DTFWYKFLQR EPGGELHWEG 100
NGPHHDRCCT YNEDNLVDGV YCLPVGHWIE ATGHTNEMKH TTDFYFNIAG 150
HQAMHYSRIL PNIWLGSCPR QLEHVTIKLK HELGVTAVMN FQTEWDIIQN 200
SSGCNRYPEP MTPDTMMKLY KEEGLSYIWM PTPDMSTEGR VQMLPQAVCL 250
LHALLENGHT VYVHCNAGVG RSTAAVCGWL HYVIGWNLRK VQYFIMAKRP 300
AVYIDEDALA QAQQDFSQKF GKVHSSICAL 330
Length:330
Mass (Da):36,958
Last modified:October 3, 2012 - v2
Checksum:i89B18C64BBBAB02A
GO

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti140 – 1401H → R in AAD26336. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF124044 mRNA. Translation: AAD26336.1.
AC101984 Genomic DNA. No translation available.
AC157018 Genomic DNA. No translation available.
CH466562 Genomic DNA. Translation: EDL03516.1.
AK041609 mRNA. Translation: BAC31004.1.
CCDSiCCDS23698.1.
RefSeqiNP_034276.2. NM_010146.2.
UniGeneiMm.89946.

Genome annotation databases

EnsembliENSMUST00000069106; ENSMUSP00000066050; ENSMUSG00000055493.
GeneIDi13853.
KEGGimmu:13853.
UCSCiuc007ejv.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF124044 mRNA. Translation: AAD26336.1 .
AC101984 Genomic DNA. No translation available.
AC157018 Genomic DNA. No translation available.
CH466562 Genomic DNA. Translation: EDL03516.1 .
AK041609 mRNA. Translation: BAC31004.1 .
CCDSi CCDS23698.1.
RefSeqi NP_034276.2. NM_010146.2.
UniGenei Mm.89946.

3D structure databases

ProteinModelPortali Q9WUA5.
SMRi Q9WUA5. Positions 8-108, 153-300.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

IntActi Q9WUA5. 3 interactions.
MINTi MINT-8374088.

Protein family/group databases

CAZyi CBM20. Carbohydrate-Binding Module Family 20.

PTM databases

PhosphoSitei Q9WUA5.

Proteomic databases

PRIDEi Q9WUA5.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000069106 ; ENSMUSP00000066050 ; ENSMUSG00000055493 .
GeneIDi 13853.
KEGGi mmu:13853.
UCSCi uc007ejv.1. mouse.

Organism-specific databases

CTDi 7957.
MGIi MGI:1341085. Epm2a.

Phylogenomic databases

eggNOGi NOG243912.
GeneTreei ENSGT00390000010101.
HOGENOMi HOG000285975.
HOVERGENi HBG051493.
InParanoidi Q9WUA5.
KOi K14165.
OMAi HWIEVSG.
OrthoDBi EOG7RJPRM.
TreeFami TF332841.

Enzyme and pathway databases

Reactomei REACT_188939. Glycogen synthesis.
REACT_203841. Myoclonic epilepsy of Lafora.

Miscellaneous databases

NextBioi 284714.
PROi Q9WUA5.
SOURCEi Search...

Gene expression databases

Genevestigatori Q9WUA5.

Family and domain databases

Gene3Di 2.60.40.10. 1 hit.
3.90.190.10. 1 hit.
InterProi IPR013784. Carb-bd-like_fold.
IPR002044. CBM_fam20.
IPR000340. Dual-sp_phosphatase_cat-dom.
IPR020422. Dual-sp_phosphatase_subgr_cat.
IPR024950. DUSP.
IPR013783. Ig-like_fold.
IPR029021. Prot-tyrosine_phosphatase-like.
IPR000387. Tyr/Dual-sp_Pase.
IPR016130. Tyr_Pase_AS.
[Graphical view ]
PANTHERi PTHR10159. PTHR10159. 1 hit.
Pfami PF00686. CBM_20. 1 hit.
PF00782. DSPc. 1 hit.
[Graphical view ]
SMARTi SM01065. CBM_2. 1 hit.
[Graphical view ]
SUPFAMi SSF49452. SSF49452. 1 hit.
SSF52799. SSF52799. 1 hit.
PROSITEi PS51166. CBM20. 1 hit.
PS00383. TYR_PHOSPHATASE_1. 1 hit.
PS50056. TYR_PHOSPHATASE_2. 1 hit.
PS50054. TYR_PHOSPHATASE_DUAL. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A."
    Ganesh S., Amano K., Delgado-Escueta A.V., Yamakawa K.
    Biochem. Biophys. Res. Commun. 257:24-28(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
    Strain: ICR.
    Tissue: Brain.
  2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  3. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 10-137.
    Strain: C57BL/6J.
    Tissue: Thymus.
  5. "Regional and developmental expression of Epm2a gene and its evolutionary conservation."
    Ganesh S., Agarwala K.L., Amano K., Suzuki T., Delgado-Escueta A.V., Yamakawa K.
    Biochem. Biophys. Res. Commun. 283:1046-1053(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: DEVELOPMENTAL STAGE.
  6. "Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy."
    Chan E.M., Ackerley C.A., Lohi H., Ianzano L., Cortez M.A., Shannon P., Scherer S.W., Minassian B.A.
    Hum. Mol. Genet. 13:1117-1129(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION, INTERACTION WITH POLYGLUCOSANS AND GLYCOGEN.
  7. "Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo."
    Tagliabracci V.S., Turnbull J., Wang W., Girard J.M., Zhao X., Skurat A.V., Delgado-Escueta A.V., Minassian B.A., Depaoli-Roach A.A., Roach P.J.
    Proc. Natl. Acad. Sci. U.S.A. 104:19262-19266(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS A GLUCAN PHOSPHATASE, DISRUPTION PHENOTYPE, ACTIVE SITE, MUTAGENESIS OF TRP-32 AND CYS-265.
  8. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  9. "The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system."
    Garyali P., Siwach P., Singh P.K., Puri R., Mittal S., Sengupta S., Parihar R., Ganesh S.
    Hum. Mol. Genet. 18:688-700(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, COMPLEX FORMATION WITH NHLRC1 AND HSP70.
  10. "Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an animal model for Lafora disease."
    Puri R., Suzuki T., Yamakawa K., Ganesh S.
    J. Biol. Chem. 284:22657-22663(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH MAPT, DISRUPTION PHENOTYPE.
  11. "Laforin, the most common protein mutated in Lafora disease, regulates autophagy."
    Aguado C., Sarkar S., Korolchuk V.I., Criado O., Vernia S., Boya P., Sanz P., de Cordoba S.R., Knecht E., Rubinsztein D.C.
    Hum. Mol. Genet. 19:2867-2876(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  12. "Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease."
    Tiberia E., Turnbull J., Wang T., Ruggieri A., Zhao X.C., Pencea N., Israelian J., Wang Y., Ackerley C.A., Wang P., Liu Y., Minassian B.A.
    J. Biol. Chem. 287:25650-25659(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  13. "Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex."
    Rubio-Villena C., Garcia-Gimeno M.A., Sanz P.
    Int. J. Biochem. Cell Biol. 45:1479-1488(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH PPP1R3D.

Entry informationi

Entry nameiEPM2A_MOUSE
AccessioniPrimary (citable) accession number: Q9WUA5
Secondary accession number(s): G5E8E2, Q8BY80
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: October 3, 2012
Last modified: September 3, 2014
This is version 108 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi