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Protein

Laforin

Gene

Epm2a

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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.PROSITE-ProRule annotation
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei265 – 2651Phosphocysteine intermediatePROSITE-ProRule annotation1 Publication
Sitei328 – 3281Required for homodimerizationBy similarity

GO - Molecular functioni

GO - Biological processi

  • autophagy Source: UniProtKB-KW
  • glycogen metabolic process Source: UniProtKB-KW
  • habituation Source: MGI
  • inositol phosphate dephosphorylation Source: GO_Central
  • nervous system development Source: MGI
  • peptidyl-tyrosine dephosphorylation Source: MGI
  • protein dephosphorylation Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protein phosphatase

Keywords - Biological processi

Autophagy, Carbohydrate metabolism, Glycogen metabolism

Enzyme and pathway databases

ReactomeiREACT_292921. Glycogen synthesis.

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 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1341085. Epm2a.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: MGI
  • endoplasmic reticulum Source: UniProtKB-SubCell
  • nucleus Source: MGI
  • polysome Source: MGI
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 AMPKBy 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

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.By similarity3 Publications

Binary interactionsi

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

Protein-protein interaction databases

BioGridi199484. 4 interactions.
IntActiQ9WUA5. 3 interactions.
MINTiMINT-8374088.
STRINGi10090.ENSMUSP00000066050.

Structurei

3D structure databases

ProteinModelPortaliQ9WUA5.
SMRiQ9WUA5. Positions 1-330.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1 – 123123CBM20PROSITE-ProRule annotationAdd
BLAST
Domaini242 – 31069Tyrosine-protein phosphataseAdd
BLAST

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiNOG243912.
GeneTreeiENSGT00390000010101.
HOGENOMiHOG000285975.
HOVERGENiHBG051493.
InParanoidiQ9WUA5.
KOiK14165.
OMAiQAVFLLH.
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

        10         20         30         40         50
MLFRFGVVVP PAVAGARQEL LLAGSRPELG RWEPHGAVRL RPAGTAAGAA
60 70 80 90 100
ALALQEPGLW LAEVELEAYE EAGGAEPGRV DTFWYKFLQR EPGGELHWEG
110 120 130 140 150
NGPHHDRCCT YNEDNLVDGV YCLPVGHWIE ATGHTNEMKH TTDFYFNIAG
160 170 180 190 200
HQAMHYSRIL PNIWLGSCPR QLEHVTIKLK HELGVTAVMN FQTEWDIIQN
210 220 230 240 250
SSGCNRYPEP MTPDTMMKLY KEEGLSYIWM PTPDMSTEGR VQMLPQAVCL
260 270 280 290 300
LHALLENGHT VYVHCNAGVG RSTAAVCGWL HYVIGWNLRK VQYFIMAKRP
310 320 330
AVYIDEDALA QAQQDFSQKF GKVHSSICAL
Length:330
Mass (Da):36,958
Last modified:October 3, 2012 - v2
Checksum:i89B18C64BBBAB02A
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti140 – 1401H → R in AAD26336 (PubMed:10092504).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

ProteinModelPortaliQ9WUA5.
SMRiQ9WUA5. Positions 1-330.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi199484. 4 interactions.
IntActiQ9WUA5. 3 interactions.
MINTiMINT-8374088.
STRINGi10090.ENSMUSP00000066050.

Protein family/group databases

CAZyiCBM20. Carbohydrate-Binding Module Family 20.

PTM databases

PhosphoSiteiQ9WUA5.

Proteomic databases

PRIDEiQ9WUA5.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi7957.
MGIiMGI:1341085. Epm2a.

Phylogenomic databases

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

Enzyme and pathway databases

ReactomeiREACT_292921. Glycogen synthesis.

Miscellaneous databases

NextBioi284714.
PROiQ9WUA5.
SOURCEiSearch...

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]
ProtoNetiSearch...

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: June 24, 2015
This is version 115 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

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.