EPM2A_CANLF
ID EPM2A_CANLF Reviewed; 331 AA.
AC Q1M199;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2006, sequence version 1.
DT 03-AUG-2022, entry version 85.
DE RecName: Full=Laforin;
DE EC=3.1.3.- {ECO:0000250|UniProtKB:Q9WUA5};
DE EC=3.1.3.16;
DE EC=3.1.3.48 {ECO:0000250|UniProtKB:O95278};
DE AltName: Full=Glucan phosphatase;
DE AltName: Full=Lafora PTPase;
DE Short=LAFPTPase;
GN Name=EPM2A;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=15637270; DOI=10.1126/science.1102832;
RA Lohi H., Young E.J., Fitzmaurice S.N., Rusbridge C., Chan E.M.,
RA Vervoort M., Turnbull J., Zhao X.C., Ianzano L., Paterson A.D.,
RA Sutter N.B., Ostrander E.A., Andre C., Shelton G.D., Ackerley C.A.,
RA Scherer S.W., Minassian B.A.;
RT "Expanded repeat in canine epilepsy.";
RL Science 307:81-81(2005).
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. Dephosphorylates phosphotyrosine
CC and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and
CC has low activity with phosphoserine and phosphothreonine substrates (in
CC vitro). Has also been shown to dephosphorylate MAPT. Shows strong
CC phosphatase activity towards complex carbohydrates in vitro, avoiding
CC glycogen hyperphosphorylation which is associated with reduced
CC branching and formation of insoluble aggregates. Forms a complex with
CC NHLRC1/malin and HSP70, which suppresses the cellular toxicity of
CC misfolded proteins by promoting their degradation through the
CC ubiquitin-proteasome system (UPS). 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. {ECO:0000250|UniProtKB:O95278, ECO:0000250|UniProtKB:Q9WUA5}.
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};
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. Interacts with itself. Interacts with PPP1R3B,
CC PPP1R3C, PPP1R3D, HIRIP5, and EPM2AIP1. Binds glycogen and Lafora
CC bodies. Interacts with NHLRC1/malin (via the NHL repeats). Forms a
CC complex with NHLRC1/malin and HSP70. Interacts with PPP1R3D; in the
CC presence of NHLC1/malin the interaction leads to ubiquitination and
CC autophagic degradation of PPP1R3D. Interacts (via the phosphatase
CC domain) with MAPT/Tau; the interaction dephosphorylates MAPT. Interacts
CC with PRDM8. {ECO:0000250|UniProtKB:O95278}.
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 -!- 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 -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC {ECO:0000305}.
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DR EMBL; AY560906; ABE98181.1; -; Genomic_DNA.
DR AlphaFoldDB; Q1M199; -.
DR SMR; Q1M199; -.
DR STRING; 9612.ENSCAFP00000030595; -.
DR CAZy; CBM20; Carbohydrate-Binding Module Family 20.
DR PaxDb; Q1M199; -.
DR Ensembl; ENSCAFT00030033597; ENSCAFP00030029318; ENSCAFG00030018154.
DR eggNOG; KOG1716; Eukaryota.
DR InParanoid; Q1M199; -.
DR Proteomes; UP000002254; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0098556; C:cytoplasmic side of rough endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030246; F:carbohydrate binding; ISS:UniProtKB.
DR GO; GO:0019203; F:carbohydrate phosphatase activity; ISS:UniProtKB.
DR GO; GO:2001069; F:glycogen binding; ISS:UniProtKB.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IBA:GO_Central.
DR GO; GO:0008138; F:protein tyrosine/serine/threonine phosphatase activity; IEA:InterPro.
DR GO; GO:2001070; F:starch binding; IEA:InterPro.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0016311; P:dephosphorylation; ISS:UniProtKB.
DR GO; GO:0005977; P:glycogen metabolic process; ISS:UniProtKB.
DR GO; GO:0046838; P:phosphorylated carbohydrate dephosphorylation; ISS:UniProtKB.
DR GO; GO:0006470; P:protein dephosphorylation; IEA:InterPro.
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 3: Inferred from homology;
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..331
FT /note="Laforin"
FT /id="PRO_0000289592"
FT DOMAIN 1..124
FT /note="CBM20"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00594"
FT DOMAIN 156..323
FT /note="Tyrosine-protein phosphatase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160"
FT MOTIF 266..272
FT /note="Glucan phosphatase signature motif CXAGXGR"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT ACT_SITE 266
FT /note="Phosphocysteine intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160"
FT BINDING 32
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 87
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 103..107
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 197
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 235
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 241
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 267..272
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT BINDING 304
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:O95278"
FT SITE 329
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"
SQ SEQUENCE 331 AA; 36900 MW; 788A905A6D82835B CRC64;
MRFRFGVVVP PAGAGAAPEL LVVGSRPELG RWEPRGAVRL RPAGSAAGGG ARALQEPGLW
LGEVELAPGE AARDGAEPAR VDTFWYKFLK REPGGALSWE GNGPHHDRCC TYNENNLVDG
VYCLPIGHWI EATGHTNEMK HTTDFYFNIA GHQAMHYSRI LPNIWLGSCP RQVEHITIKL
KHELGITAVM NFQTEWDIVQ NSSGCNRYPE PMTPDTMIKL YKEEGLVYIW MPTPDMSTEG
RVQMLPQAVC LLHALLENGH TVYVHCNAGV GRSTAAVCGW LQYVMGWNLR KVQYFLMAKR
PAVYIDEDAL ARAEEDFFQK FGKVRSSVCS V
