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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

Plays an important role in preventing glycogen hyperphosphorylation and the formation of insoluble aggregates, via its activity as glycogen phosphatase, and by promoting the ubiquitination of proteins involved in glycogen metabolism via its interaction with the E3 ubiquitin ligase NHLRC1/malin (PubMed:18040046, PubMed:18852261, PubMed:19036738, PubMed:23663739, PubMed:24430976, PubMed:24068615). Dephosphorylates phosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity with phosphoserine and phosphothreonine substrates (in vitro) (PubMed:16971387, PubMed:24430976). Has also been shown to dephosphorylate MAPT (PubMed:19542233). Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates (PubMed:18040046, PubMed:18852261, PubMed:23663739). 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) (PubMed:19036738, PubMed:24068615). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway (PubMed:20453062).10 Publications

Catalytic activityi

Protein tyrosine phosphate + H2O = protein tyrosine + phosphate.PROSITE-ProRule annotation1 Publication
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei32SubstrateBy similarity1
Binding sitei86SubstrateBy similarity1
Binding sitei196SubstrateBy similarity1
Binding sitei234SubstrateBy similarity1
Binding sitei240SubstrateBy similarity1
Active sitei265Phosphocysteine intermediatePROSITE-ProRule annotation2 Publications1
Binding sitei303SubstrateBy similarity1
Sitei328Required for homodimerizationBy similarity1

GO - Molecular functioni

GO - Biological processi

  • autophagy Source: UniProtKB-KW
  • glycogen metabolic process Source: UniProtKB
  • habituation Source: MGI
  • negative regulation of TOR signaling Source: MGI
  • nervous system development Source: MGI
  • phosphorylated carbohydrate dephosphorylation Source: UniProtKB
  • positive regulation of macroautophagy Source: MGI
  • protein dephosphorylation Source: MGI

Keywordsi

Molecular functionHydrolase, Protein phosphatase
Biological processAutophagy, Carbohydrate metabolism, Glycogen metabolism

Enzyme and pathway databases

ReactomeiR-MMU-3322077. Glycogen synthesis.

Protein family/group databases

CAZyiCBM20. Carbohydrate-Binding Module Family 20.

Names & Taxonomyi

Protein namesi
Recommended name:
Laforin1 Publication (EC:3.1.3.-3 Publications, EC:3.1.3.16, EC:3.1.3.481 Publication)
Alternative name(s):
Glucan phosphatase
Lafora PTPase
Short name:
LAFPTPase
Gene namesi
Name:Epm2a
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1341085. Epm2a.

Subcellular locationi

  • Cytoplasm By similarity
  • Endoplasmic reticulum membrane By similarity; Peripheral membrane protein By similarity; Cytoplasmic side By similarity
  • Cell membrane By similarity

  • Note: Colocalizes with glycogen synthase in punctate structures in the cytoplasm. Primarily associated with polyribosomes at the rough endoplasmic reticulum, and also detected at the plasma membrane. Under glycogenolytic conditions localizes to the nucleus.By similarity

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytoplasmic side of rough endoplasmic reticulum membrane Source: UniProtKB
  • cytosol Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
  • polysome Source: MGI

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Endoplasmic reticulum, Membrane

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 (PubMed:12019206, PubMed:18040046, PubMed:24430976). Expression of both wild-type Epm2a and mutated Epm2a without phosphatase activity can abolish the appearance of Lafora bodies in brain and heart from 7 to over 12 month old mutant mice (PubMed:24430976). 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 (PubMed:18040046, PubMed:18852261, PubMed:22669944, PubMed:23663739). Muscle glycogen has an altered structure, with a reduced size, an abnormally high proportion of very short side chains, fewer medium-length chains and an increased number of long chains (PubMed:23663739). Glycogen synthase (Gys1) and 1,4-alpha-glucan-branching enzyme (Gbe1) activities in brain and muscle tissue are normal (PubMed:18040046). 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 (PubMed:19542233). 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 (PubMed:20453062).8 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi32W → G: Loss of glycogen phosphatase activity. Nearly abolishes phosphatase activity. 2 Publications1
Mutagenesisi83F → L: Abolishes phosphatase activity. 1 Publication1
Mutagenesisi107R → C: Abolishes phosphatase activity. 1 Publication1
Mutagenesisi193T → I: Nearly abolishes phosphatase activity. 1 Publication1
Mutagenesisi265C → S: Loss of phosphatase activity with glycogen and synthetic substrates. 3 Publications1
Mutagenesisi292Q → L: Abolishes phosphatase activity. 1 Publication1
Mutagenesisi293Y → N: Nearly abolishes phosphatase activity. 1 Publication1
Mutagenesisi300P → L: Abolishes phosphatase activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000948391 – 330LaforinAdd BLAST330

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei25Phosphoserine; by AMPKBy similarity1

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

PaxDbiQ9WUA5.
PRIDEiQ9WUA5.

PTM databases

PhosphoSitePlusiQ9WUA5.

Expressioni

Tissue specificityi

Detected in skeletal muscle and in brain (at protein level) (PubMed:24430976). Widely expressed. Higher levels of expression are found in heart, brain, liver, skeletal muscle and kidney (PubMed:10092504).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

BgeeiENSMUSG00000055493.
GenevisibleiQ9WUA5. MM.

Interactioni

Subunit structurei

Homodimer (PubMed:16971387). Interacts with PPP1R3B, PPP1R3C, HIRIP5, and EPM2AIP1 (By similarity). Binds glycogen and Lafora bodies. Interacts with NHLRC1/malin (via the NHL repeats) (By similarity). Forms a complex with NHLRC1/malin and HSP70 (PubMed:19036738). Interacts with PPP1R3D; in the presence of NHLC1/malin the interaction leads to ubiquitination and autophagic degradation of PPP1R3D (PubMed:23624058). Interacts (via the phosphatase domain) with MAPT/Tau; the interaction dephosphorylates MAPT (PubMed:19542233). Interacts with PRDM8 (By similarity).By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi199484. 3 interactors.
IntActiQ9WUA5. 3 interactors.
MINTiMINT-8374088.
STRINGi10090.ENSMUSP00000066050.

Structurei

3D structure databases

ProteinModelPortaliQ9WUA5.
SMRiQ9WUA5.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 123CBM20PROSITE-ProRule annotationAdd BLAST123
Domaini242 – 310Tyrosine-protein phosphataseAdd BLAST69

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni102 – 106Substrate bindingBy similarity5
Regioni266 – 271Substrate bindingBy similarity6

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi265 – 271Glucan phosphatase signature motif CXAGXGRBy similarity7

Domaini

The CBM20 domain mediates binding to cytoplasmic glycogen and to Lafora polyglucosan bodies.By similarity

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG1716. Eukaryota.
COG2453. LUCA.
GeneTreeiENSGT00390000010101.
HOGENOMiHOG000285975.
HOVERGENiHBG051493.
InParanoidiQ9WUA5.
KOiK14165.
OMAiGHTDEMK.
OrthoDBiEOG091G0GBM.
TreeFamiTF332841.

Family and domain databases

CDDicd05806. CBM20_laforin. 1 hit.
Gene3Di2.60.40.10. 1 hit.
3.90.190.10. 1 hit.
InterProiView protein in InterPro
IPR013784. Carb-bd-like_fold.
IPR034831. CBM20_laforin.
IPR002044. CBM_fam20.
IPR000340. Dual-sp_phosphatase_cat-dom.
IPR024950. DUSP.
IPR013783. Ig-like_fold.
IPR029021. Prot-tyrosine_phosphatase-like.
IPR016130. Tyr_Pase_AS.
IPR000387. TYR_PHOSPHATASE_dom.
IPR020422. TYR_PHOSPHATASE_DUAL_dom.
PANTHERiPTHR10159. PTHR10159. 1 hit.
PfamiView protein in Pfam
PF00686. CBM_20. 1 hit.
PF00782. DSPc. 1 hit.
SMARTiView protein in SMART
SM01065. CBM_2. 1 hit.
SM00195. DSPc. 1 hit.
SUPFAMiSSF49452. SSF49452. 1 hit.
SSF52799. SSF52799. 1 hit.
PROSITEiView protein in PROSITE
PS51166. CBM20. 1 hit.
PS00383. TYR_PHOSPHATASE_1. 1 hit.
PS50056. TYR_PHOSPHATASE_2. 1 hit.
PS50054. TYR_PHOSPHATASE_DUAL. 1 hit.

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)DescriptionActionsGraphical viewLength
Sequence conflicti140H → R in AAD26336 (PubMed:10092504).Curated1

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.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi199484. 3 interactors.
IntActiQ9WUA5. 3 interactors.
MINTiMINT-8374088.
STRINGi10090.ENSMUSP00000066050.

Protein family/group databases

CAZyiCBM20. Carbohydrate-Binding Module Family 20.

PTM databases

PhosphoSitePlusiQ9WUA5.

Proteomic databases

PaxDbiQ9WUA5.
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

eggNOGiKOG1716. Eukaryota.
COG2453. LUCA.
GeneTreeiENSGT00390000010101.
HOGENOMiHOG000285975.
HOVERGENiHBG051493.
InParanoidiQ9WUA5.
KOiK14165.
OMAiGHTDEMK.
OrthoDBiEOG091G0GBM.
TreeFamiTF332841.

Enzyme and pathway databases

ReactomeiR-MMU-3322077. Glycogen synthesis.

Miscellaneous databases

PROiPR:Q9WUA5.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000055493.
GenevisibleiQ9WUA5. MM.

Family and domain databases

CDDicd05806. CBM20_laforin. 1 hit.
Gene3Di2.60.40.10. 1 hit.
3.90.190.10. 1 hit.
InterProiView protein in InterPro
IPR013784. Carb-bd-like_fold.
IPR034831. CBM20_laforin.
IPR002044. CBM_fam20.
IPR000340. Dual-sp_phosphatase_cat-dom.
IPR024950. DUSP.
IPR013783. Ig-like_fold.
IPR029021. Prot-tyrosine_phosphatase-like.
IPR016130. Tyr_Pase_AS.
IPR000387. TYR_PHOSPHATASE_dom.
IPR020422. TYR_PHOSPHATASE_DUAL_dom.
PANTHERiPTHR10159. PTHR10159. 1 hit.
PfamiView protein in Pfam
PF00686. CBM_20. 1 hit.
PF00782. DSPc. 1 hit.
SMARTiView protein in SMART
SM01065. CBM_2. 1 hit.
SM00195. DSPc. 1 hit.
SUPFAMiSSF49452. SSF49452. 1 hit.
SSF52799. SSF52799. 1 hit.
PROSITEiView protein in PROSITE
PS51166. CBM20. 1 hit.
PS00383. TYR_PHOSPHATASE_1. 1 hit.
PS50056. TYR_PHOSPHATASE_2. 1 hit.
PS50054. TYR_PHOSPHATASE_DUAL. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiEPM2A_MOUSE
AccessioniPrimary (citable) accession number: Q9WUA5
Secondary accession number(s): G5E8E2, Q8BY80
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: October 3, 2012
Last modified: June 7, 2017
This is version 131 of the entry and version 2 of the sequence. See 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

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 one 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.