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Q9WUA5 (EPM2A_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 104. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Epm2a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length330 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12

Catalytic activity

Protein tyrosine phosphate + H2O = protein tyrosine + phosphate.

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

Subunit structure

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. Ref.6 Ref.10 Ref.13

Subcellular location

Cytoplasm. Endoplasmic reticulum. Note: Under glycogenolytic conditions localizes to the nucleus By similarity. Ref.6

Tissue specificity

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. Ref.1 Ref.6

Developmental stage

In the embryo, highly expressed at 17 dpc. Detected in all postnatal stages, but highest expression is found at day 160 after birth. Ref.5

Post-translational modification

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.

Disruption phenotype

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. Ref.7 Ref.8 Ref.10 Ref.11 Ref.12

Sequence similarities

Belongs to the protein-tyrosine phosphatase family.

Contains 1 CBM20 (carbohydrate binding type-20) domain.

Contains 1 tyrosine-protein phosphatase domain.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Gsk3bQ9WV602EBI-1040928,EBI-400793
NHLRC1Q6VVB112EBI-1040928,EBI-6426628From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 330330Laforin
PRO_0000094839

Regions

Domain1 – 123123CBM20
Domain242 – 31069Tyrosine-protein phosphatase

Sites

Active site2651Phosphocysteine intermediate Ref.7
Site3281Required for homodimerization By similarity

Amino acid modifications

Modified residue251Phosphoserine; by AMPK By similarity

Experimental info

Mutagenesis321W → G: Loss of glycogen phosphatase activity. Ref.7
Mutagenesis2651C → S: Loss of glycogen phosphatase activity. Ref.7
Sequence conflict1401H → R in AAD26336. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q9WUA5 [UniParc].

Last modified October 3, 2012. Version 2.
Checksum: 89B18C64BBBAB02A

FASTA33036,958
        10         20         30         40         50         60 
MLFRFGVVVP PAVAGARQEL LLAGSRPELG RWEPHGAVRL RPAGTAAGAA ALALQEPGLW 

        70         80         90        100        110        120 
LAEVELEAYE EAGGAEPGRV DTFWYKFLQR EPGGELHWEG NGPHHDRCCT YNEDNLVDGV 

       130        140        150        160        170        180 
YCLPVGHWIE ATGHTNEMKH TTDFYFNIAG HQAMHYSRIL PNIWLGSCPR QLEHVTIKLK 

       190        200        210        220        230        240 
HELGVTAVMN FQTEWDIIQN SSGCNRYPEP MTPDTMMKLY KEEGLSYIWM PTPDMSTEGR 

       250        260        270        280        290        300 
VQMLPQAVCL LHALLENGHT VYVHCNAGVG RSTAAVCGWL HYVIGWNLRK VQYFIMAKRP 

       310        320        330 
AVYIDEDALA QAQQDFSQKF GKVHSSICAL 

« Hide

References

« Hide 'large scale' references
[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]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
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. expand/collapse author list , 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]"Abnormal metabolism of glycogen phosphate as a cause for Lafora disease."
Tagliabracci V.S., Girard J.M., Segvich D., Meyer C., Turnbull J., Zhao X., Minassian B.A., Depaoli-Roach A.A., Roach P.J.
J. Biol. Chem. 283:33816-33825(2008) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_034276.2. NM_010146.2.
UniGeneMm.89946.

3D structure databases

ProteinModelPortalQ9WUA5.
SMRQ9WUA5. Positions 8-108, 153-300.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ9WUA5. 3 interactions.
MINTMINT-8374088.

Protein family/group databases

CAZyCBM20. Carbohydrate-Binding Module Family 20.

PTM databases

PhosphoSiteQ9WUA5.

Proteomic databases

PRIDEQ9WUA5.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000069106; ENSMUSP00000066050; ENSMUSG00000055493.
GeneID13853.
KEGGmmu:13853.
UCSCuc007ejv.1. mouse.

Organism-specific databases

CTD7957.
MGIMGI:1341085. Epm2a.

Phylogenomic databases

eggNOGNOG243912.
GeneTreeENSGT00390000010101.
HOGENOMHOG000285975.
HOVERGENHBG051493.
InParanoidQ9WUA5.
KOK14165.
OMARKVQYFV.
OrthoDBEOG7RJPRM.
TreeFamTF332841.

Gene expression databases

GenevestigatorQ9WUA5.

Family and domain databases

Gene3D2.60.40.10. 1 hit.
InterProIPR013784. 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.
IPR000387. Tyr/Dual-sp_Pase.
IPR016130. Tyr_Pase_AS.
[Graphical view]
PANTHERPTHR10159. PTHR10159. 1 hit.
PfamPF00686. CBM_20. 1 hit.
PF00782. DSPc. 1 hit.
[Graphical view]
SMARTSM01065. CBM_2. 1 hit.
[Graphical view]
SUPFAMSSF49452. SSF49452. 1 hit.
PROSITEPS51166. CBM20. 1 hit.
PS00383. TYR_PHOSPHATASE_1. 1 hit.
PS50056. TYR_PHOSPHATASE_2. 1 hit.
PS50054. TYR_PHOSPHATASE_DUAL. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio284714.
PROQ9WUA5.
SOURCESearch...

Entry information

Entry nameEPM2A_MOUSE
AccessionPrimary (citable) accession number: Q9WUA5
Secondary accession number(s): G5E8E2, Q8BY80
Entry history
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: October 3, 2012
Last modified: April 16, 2014
This is version 104 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot