EPM2A_HUMAN
ID EPM2A_HUMAN Reviewed; 331 AA.
AC O95278; B3KMU5; B4DRZ2; O95483; Q5T3F5; Q6IS15; Q8IU96; Q8IX24; Q8IX25;
AC Q9BS66; Q9UEN2;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 2.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Laforin {ECO:0000303|PubMed:11001928};
DE EC=3.1.3.- {ECO:0000269|PubMed:16901901, ECO:0000269|PubMed:23922729, ECO:0000269|PubMed:25538239, ECO:0000269|PubMed:25544560, ECO:0000269|PubMed:26231210};
DE EC=3.1.3.16 {ECO:0000305|PubMed:11001928};
DE EC=3.1.3.48 {ECO:0000269|PubMed:11001928, ECO:0000269|PubMed:11220751};
DE AltName: Full=Glucan phosphatase {ECO:0000303|PubMed:16901901, ECO:0000303|PubMed:25538239};
DE AltName: Full=Glycogen phosphatase {ECO:0000303|PubMed:25538239, ECO:0000303|PubMed:25544560};
DE AltName: Full=Lafora PTPase;
DE Short=LAFPTPase {ECO:0000303|PubMed:11175283};
GN Name=EPM2A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), ALTERNATIVE SPLICING, TISSUE
RP SPECIFICITY, VARIANTS EPM2 CYS-108; SER-279 AND LEU-293, AND VARIANT
RP ASP-114.
RX PubMed=9771710; DOI=10.1038/2470;
RA Minassian B.A., Lee J.R., Herbrick J.-A., Huizenga J., Soder S.,
RA Mungall A.J., Dunham I., Gardner R., Fong C.G., Carpenter S., Jardim L.,
RA Satishchandra P., Andermann E., Snead O.C. III, Lopes-Cendes I.,
RA Tsui L.-C., Delgado-Escueta A.V., Rouleau G.A., Scherer S.W.;
RT "Mutations in a gene encoding a novel protein tyrosine phosphatase cause
RT progressive myoclonus epilepsy.";
RL Nat. Genet. 20:171-174(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTIONAL CHARACTERIZATION,
RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS
RP EPM2 HIS-171 AND LEU-293.
RC TISSUE=Fetal brain;
RX PubMed=11001928; DOI=10.1093/oxfordjournals.hmg.a018916;
RA Ganesh S., Agarwala K.L., Ueda K., Akagi T., Shoda K., Usui T.,
RA Hashikawa T., Osada H., Delgado-Escueta A.V., Yamakawa K.;
RT "Laforin, defective in the progressive myoclonus epilepsy of Lafora type,
RT is a dual-specificity phosphatase associated with polyribosomes.";
RL Hum. Mol. Genet. 9:2251-2261(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Lee J.R., Scherer S.W.;
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8), AND NUCLEOTIDE SEQUENCE [MRNA] OF
RP 25-331 (ISOFORM 4).
RC TISSUE=Cerebellum, and Fetal brain;
RA Ganesh S., Yamakawa K.;
RT "Cloning of differentially spliced transcripts of the EPM2A gene.";
RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 7 AND 8).
RC TISSUE=Fetal brain, and Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 6).
RC TISSUE=Hypothalamus, and Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 82-331 (ISOFORMS 1 AND 2), AND VARIANTS EPM2
RP HIS-171; ILE-194; SER-279 AND ASN-294.
RX PubMed=9931343; DOI=10.1093/hmg/8.2.345;
RA Serratosa J.M., Gomez-Garre P., Gallardo M.E., Anta B., de Bernabe D.B.,
RA Lindhout D., Augustijn P.B., Tassinari C.A., Malafosse R.M., Topcu M.,
RA Grid D., Dravet C., Berkovic S.F., de Cordoba S.R.;
RT "A novel protein tyrosine phosphatase gene is mutated in progressive
RT myoclonus epilepsy of the Lafora type (EPM2).";
RL Hum. Mol. Genet. 8:345-352(1999).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF CYS-266,
RP AND ACTIVE SITE.
RX PubMed=11220751;
RX DOI=10.1002/1531-8249(20010201)49:2<271::aid-ana52>3.0.co;2-d;
RA Minassian B.A., Andrade D.M., Ianzano L., Young E.J., Chan E.,
RA Ackerley C.A., Scherer S.W.;
RT "Laforin is a cell membrane and endoplasmic reticulum-associated protein
RT tyrosine phosphatase.";
RL Ann. Neurol. 49:271-275(2001).
RN [11]
RP ALTERNATIVE SPLICING, AND SUBCELLULAR LOCATION (ISOFORM 2).
RX PubMed=11883934; DOI=10.1006/bbrc.2002.6590;
RA Ganesh S., Suzuki T., Yamakawa K.;
RT "Alternative splicing modulates subcellular localization of laforin.";
RL Biochem. Biophys. Res. Commun. 291:1134-1137(2002).
RN [12]
RP GLYCOGEN-BINDING, DOMAIN, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT
RP EPM2 GLY-32, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF LYS-87 AND
RP CYS-266.
RX PubMed=11739371; DOI=10.1074/jbc.c100686200;
RA Wang J., Stuckey J.A., Wishart M.J., Dixon J.E.;
RT "A unique carbohydrate binding domain targets the Lafora disease
RT phosphatase to glycogen.";
RL J. Biol. Chem. 277:2377-2380(2002).
RN [13]
RP INTERACTION WITH EPM2AIP1.
RX PubMed=12782127; DOI=10.1016/s0888-7543(03)00094-6;
RA Ianzano L., Zhao X.C., Minassian B.A., Scherer S.W.;
RT "Identification of a novel protein interacting with laforin, the EPM2A
RT progressive myoclonus epilepsy gene product.";
RL Genomics 81:579-587(2003).
RN [14]
RP INTERACTION WITH HIRIP5.
RX PubMed=12915448; DOI=10.1093/hmg/ddg253;
RA Ganesh S., Tsurutani N., Suzuki T., Ueda K., Agarwala K.L., Osada H.,
RA Delgado-Escueta A.V., Yamakawa K.;
RT "The Lafora disease gene product laforin interacts with HIRIP5, a
RT phylogenetically conserved protein containing a NifU-like domain.";
RL Hum. Mol. Genet. 12:2359-2368(2003).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, SELF-INTERACTION, SUBCELLULAR LOCATION,
RP GLYCOGEN-BINDING, INTERACTION WITH PPP1R3C, TISSUE SPECIFICITY, MUTAGENESIS
RP OF ASP-235 AND CYS-266, ACTIVE SITE, AND CHARACTERIZATION OF VARIANTS EPM2
RP GLY-32; LEU-84; CYS-108; ILE-194; SER-240; SER-279; LEU-293; ASN-294 AND
RP LEU-301.
RX PubMed=14532330; DOI=10.1093/hmg/ddg340;
RA Fernandez-Sanchez M.E., Criado-Garcia O., Heath K.E., Garcia-Fojeda B.,
RA Medrano-Fernandez I., Gomez-Garre P., Sanz P., Serratosa J.M.,
RA Rodriguez de Cordoba S.;
RT "Laforin, the dual-phosphatase responsible for Lafora disease, interacts
RT with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances
RT glycogen accumulation.";
RL Hum. Mol. Genet. 12:3161-3171(2003).
RN [16]
RP BINDING TO GLYCOGEN AND LAFORA BODIES, DOMAIN, CHARACTERIZATION OF VARIANTS
RP EPM2 PRO-25; LYS-28; GLY-32 AND LEU-88, AND CHARACTERIZATION OF VARIANT
RP PRO-46.
RX PubMed=14706656; DOI=10.1016/j.bbrc.2003.12.043;
RA Ganesh S., Tsurutani N., Suzuki T., Hoshii Y., Ishihara T.,
RA Delgado-Escueta A.V., Yamakawa K.;
RT "The carbohydrate-binding domain of Lafora disease protein targets Lafora
RT polyglucosan bodies.";
RL Biochem. Biophys. Res. Commun. 313:1101-1109(2004).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, AND BINDING TO LAFORA GLUCAN BODIES.
RX PubMed=15102711; DOI=10.1093/hmg/ddh130;
RA Chan E.M., Ackerley C.A., Lohi H., Ianzano L., Cortez M.A., Shannon P.,
RA Scherer S.W., Minassian B.A.;
RT "Laforin preferentially binds the neurotoxic starch-like polyglucosans,
RT which form in its absence in progressive myoclonus epilepsy.";
RL Hum. Mol. Genet. 13:1117-1129(2004).
RN [18]
RP INTERACTION WITH NHLRC1, AND POLYUBIQUITINATION.
RX PubMed=15930137; DOI=10.1073/pnas.0503285102;
RA Gentry M.S., Worby C.A., Dixon J.E.;
RT "Insights into Lafora disease: malin is an E3 ubiquitin ligase that
RT ubiquitinates and promotes the degradation of laforin.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:8501-8506(2005).
RN [19]
RP FUNCTION AS A GLUCAN PHOSPHATASE, CATALYTIC ACTIVITY, AND INTERACTION WITH
RP PPP1R3B; PPP1R3C AND PPP1R3D.
RX PubMed=16901901; DOI=10.1074/jbc.m606117200;
RA Worby C.A., Gentry M.S., Dixon J.E.;
RT "Laforin, a dual specificity phosphatase that dephosphorylates complex
RT carbohydrates.";
RL J. Biol. Chem. 281:30412-30418(2006).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=16971387; DOI=10.1074/jbc.m607778200;
RA Liu Y., Wang Y., Wu C., Liu Y., Zheng P.;
RT "Dimerization of Laforin is required for its optimal phosphatase activity,
RT regulation of GSK3beta phosphorylation, and Wnt signaling.";
RL J. Biol. Chem. 281:34768-34774(2006).
RN [21]
RP SUBCELLULAR LOCATION.
RX PubMed=17908927; DOI=10.1101/gad.1553207;
RA Cheng A., Zhang M., Gentry M.S., Worby C.A., Dixon J.E., Saltiel A.R.;
RT "A role for AGL ubiquitination in the glycogen storage disorders of Lafora
RT and Cori's disease.";
RL Genes Dev. 21:2399-2409(2007).
RN [22]
RP FUNCTION (ISOFORMS 1 AND 2), CATALYTIC ACTIVITY, HOMODIMERIZATION, SUBUNIT,
RP SUBCELLULAR LOCATION, AND INTERACTION WITH NHLRC1 AND GLYCOGEN.
RX PubMed=18617530; DOI=10.1093/hmg/ddn199;
RA Dubey D., Ganesh S.;
RT "Modulation of functional properties of laforin phosphatase by alternative
RT splicing reveals a novel mechanism for the EPM2A gene in Lafora progressive
RT myoclonus epilepsy.";
RL Hum. Mol. Genet. 17:3010-3020(2008).
RN [23]
RP FUNCTION, AND INTERACTION WITH PPP1R3C.
RX PubMed=18070875; DOI=10.1074/jbc.m708712200;
RA Worby C.A., Gentry M.S., Dixon J.E.;
RT "Malin decreases glycogen accumulation by promoting the degradation of
RT protein targeting to glycogen (PTG).";
RL J. Biol. Chem. 283:4069-4076(2008).
RN [24]
RP FUNCTION, AND COMPLEX FORMATION WITH NHLRC1 AND HSP70.
RX PubMed=19036738; DOI=10.1093/hmg/ddn398;
RA Garyali P., Siwach P., Singh P.K., Puri R., Mittal S., Sengupta S.,
RA Parihar R., Ganesh S.;
RT "The malin-laforin complex suppresses the cellular toxicity of misfolded
RT proteins by promoting their degradation through the ubiquitin-proteasome
RT system.";
RL Hum. Mol. Genet. 18:688-700(2009).
RN [25]
RP INTERACTION WITH MAPT.
RX PubMed=19542233; DOI=10.1074/jbc.m109.009688;
RA Puri R., Suzuki T., Yamakawa K., Ganesh S.;
RT "Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an
RT animal model for Lafora disease.";
RL J. Biol. Chem. 284:22657-22663(2009).
RN [26]
RP FUNCTION.
RX PubMed=20453062; DOI=10.1093/hmg/ddq190;
RA Aguado C., Sarkar S., Korolchuk V.I., Criado O., Vernia S., Boya P.,
RA Sanz P., de Cordoba S.R., Knecht E., Rubinsztein D.C.;
RT "Laforin, the most common protein mutated in Lafora disease, regulates
RT autophagy.";
RL Hum. Mol. Genet. 19:2867-2876(2010).
RN [27]
RP PHOSPHORYLATION AT SER-25, MUTAGENESIS OF SER-25; SER-168; THR-187 AND
RP THR-194, AND INTERACTION WITH NHLRC1; PPP1R3C AND PRKAA2.
RX PubMed=21728993; DOI=10.1042/bj20110150;
RA Roma-Mateo C., Solaz-Fuster Mdel C., Gimeno-Alcaniz J.V., Dukhande V.V.,
RA Donderis J., Worby C.A., Marina A., Criado O., Koller A.,
RA Rodriguez De Cordoba S., Gentry M.S., Sanz P.;
RT "Laforin, a dual-specificity phosphatase involved in Lafora disease, is
RT phosphorylated at Ser25 by AMP-activated protein kinase.";
RL Biochem. J. 439:265-275(2011).
RN [28]
RP INTERACTION WITH PRDM8.
RX PubMed=22961547; DOI=10.1093/brain/aws205;
RA Turnbull J., Girard J.M., Lohi H., Chan E.M., Wang P., Tiberia E., Omer S.,
RA Ahmed M., Bennett C., Chakrabarty A., Tyagi A., Liu Y., Pencea N., Zhao X.,
RA Scherer S.W., Ackerley C.A., Minassian B.A.;
RT "Early-onset Lafora body disease.";
RL Brain 135:2684-2698(2012).
RN [29]
RP ALTERNATIVE SPLICING (ISOFORMS 4; 5; 6; 7 AND 9), FUNCTION (ISOFORMS 2 AND
RP 7), INTERACTION WITH NHLRC1 AND GLYCOGEN, SUBCELLULAR LOCATION, SUBUNIT,
RP CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-266, AND ACTIVE SITE.
RX PubMed=22036712; DOI=10.1016/j.ygeno.2011.10.001;
RA Dubey D., Parihar R., Ganesh S.;
RT "Identification and characterization of novel splice variants of the human
RT EPM2A gene mutated in Lafora progressive myoclonus epilepsy.";
RL Genomics 99:36-43(2012).
RN [30]
RP FUNCTION, AND INTERACTION WITH PPP1R3D.
RX PubMed=23624058; DOI=10.1016/j.biocel.2013.04.019;
RA Rubio-Villena C., Garcia-Gimeno M.A., Sanz P.;
RT "Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is
RT modulated by the laforin-malin complex.";
RL Int. J. Biochem. Cell Biol. 45:1479-1488(2013).
RN [31]
RP CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH NHLRC1, SUBUNIT, AND
RP MUTAGENESIS OF 109-CYS-CYS-110; CYS-123; CYS-169; CYS-205; CYS-250;
RP CYS-266; CYS-329 AND 329-CYS--CYS-331.
RX PubMed=23922729; DOI=10.1371/journal.pone.0069523;
RA Sanchez-Martin P., Raththagala M., Bridges T.M., Husodo S., Gentry M.S.,
RA Sanz P., Roma-Mateo C.;
RT "Dimerization of the glucan phosphatase laforin requires the participation
RT of cysteine 329.";
RL PLoS ONE 8:E69523-E69523(2013).
RN [32]
RP CATALYTIC ACTIVITY, FUNCTION, MOTIF, AND CHARACTERIZATION OF VARIANT EPM2
RP GLY-32.
RX PubMed=26231210; DOI=10.1074/jbc.m115.658203;
RA Meekins D.A., Raththagala M., Auger K.D., Turner B.D., Santelia D.,
RA Koetting O., Gentry M.S., Vander Kooi C.W.;
RT "Mechanistic insights into glucan phosphatase activity against polyglucan
RT substrates.";
RL J. Biol. Chem. 290:23361-23370(2015).
RN [33] {ECO:0007744|PDB:4R30}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 148-331, FUNCTION AS GLUCAN
RP PHOSPHATASE, CATALYTIC ACTIVITY, SUBUNIT, AND MUTAGENESIS OF CYS-169;
RP ARG-171; ASP-197; ASP-235; CYS-266; ARG-272 AND CYS-329.
RX PubMed=25538239; DOI=10.1074/jbc.m114.627406;
RA Sankhala R.S., Koksal A.C., Ho L., Nitschke F., Minassian B.A.,
RA Cingolani G.;
RT "Dimeric quaternary structure of human laforin.";
RL J. Biol. Chem. 290:4552-4559(2015).
RN [34] {ECO:0007744|PDB:4RKK}
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1-329 IN COMPLEX WITH
RP MALTOHEXAOSE AND PHOSPHATE, CATALYTIC ACTIVITY, FUNCTION, SUBUNIT,
RP MUTAGENESIS OF VAL-8; LYS-87; TRP-99; ILE-126; THR-142; ASP-197; MET-236
RP AND CYS-266, AND CHARACTERIZATION OF VARIANTS EPM2 GLY-32; HIS-171;
RP SER-240; ASN-294 AND LEU-301.
RX PubMed=25544560; DOI=10.1016/j.molcel.2014.11.020;
RA Raththagala M., Brewer M.K., Parker M.W., Sherwood A.R., Wong B.K., Hsu S.,
RA Bridges T.M., Paasch B.C., Hellman L.M., Husodo S., Meekins D.A.,
RA Taylor A.O., Turner B.D., Auger K.D., Dukhande V.V., Chakravarthy S.,
RA Sanz P., Woods V.L. Jr., Li S., Vander Kooi C.W., Gentry M.S.;
RT "Structural mechanism of laforin function in glycogen dephosphorylation and
RT lafora disease.";
RL Mol. Cell 57:261-272(2015).
RN [35]
RP VARIANTS EPM2 LEU-84; SER-240 AND LEU-301.
RX PubMed=11175283; DOI=10.1038/sj.ejhg.5200571;
RA Gomez-Garre P., Sanz Y., Rodriguez de Cordoba S.R., Serratosa J.M.;
RT "Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of
RT Lafora: high degree of allelic heterogeneity and prevalence of deletions.";
RL Eur. J. Hum. Genet. 8:946-954(2000).
RN [36]
RP VARIANT PRO-46.
RX PubMed=11735300; DOI=10.1006/mcpr.2001.0371;
RA Ganesh S., Shoda K., Amano K., Uchiyama A., Kumada S., Moriyama N.,
RA Hirose S., Yamakawa K.;
RT "Mutation screening for Japanese Lafora's disease patients: identification
RT of novel sequence variants in the coding and upstream regulatory regions of
RT EPM2A gene.";
RL Mol. Cell. Probes 15:281-289(2001).
RN [37]
RP VARIANTS EPM2 PRO-25; CYS-108; HIS-171 AND LEU-293, AND CHARACTERIZATION OF
RP VARIANTS EPM2 GLY-32; CYS-108; ILE-194; SER-279 AND ASN-294.
RX PubMed=12019207; DOI=10.1093/hmg/11.11.1263;
RA Ganesh S., Delgado-Escueta A.V., Suzuki T., Francheschetti S., Riggio C.,
RA Avanzini G., Rabinowicz A., Bohlega S., Bailey J., Alonso M.E.,
RA Rasmussen A., Thomson A.E., Ochoa A., Prado A.J., Medina M.T., Yamakawa K.;
RT "Genotype-phenotype correlations for EPM2A mutations in Lafora's
RT progressive myoclonus epilepsy: exon 1 mutations associate with an early-
RT onset cognitive deficit subphenotype.";
RL Hum. Mol. Genet. 11:1263-1271(2002).
RN [38]
RP VARIANT EPM2 ALA-187.
RX PubMed=12560877; DOI=10.1007/s100380300006;
RA Ki C.S., Kong S.Y., Seo D.W., Hong S.B., Kim H.J., Kim J.W.;
RT "Two novel mutations in the EPM2A gene in a Korean patient with Lafora's
RT progressive myoclonus epilepsy.";
RL J. Hum. Genet. 48:51-54(2003).
RN [39]
RP VARIANT EPM2 PRO-91.
RX PubMed=15009235; DOI=10.1111/j.0013-9580.2004.33203.x;
RA Annesi G., Sofia V., Gambardella A., Ciro Candiano I.C., Spadafora P.,
RA Annesi F., Cutuli N., De Marco E.V., Civitelli D., Carrideo S.,
RA Tarantino P., Barone R., Zappia M., Quattrone A.;
RT "A novel exon 1 mutation in a patient with atypical Lafora progressive
RT myoclonus epilepsy seen as childhood-onset cognitive deficit.";
RL Epilepsia 45:294-295(2004).
RN [40]
RP VARIANTS EPM2 PRO-91; HIS-171 AND SER-279, CATALYTIC ACTIVITY, AND
RP SUBCELLULAR LOCATION.
RX PubMed=14722920; DOI=10.1002/humu.10306;
RA Ianzano L., Young E.J., Zhao X.C., Chan E.M., Rodriguez M.T., Torrado M.V.,
RA Scherer S.W., Minassian B.A.;
RT "Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A)
RT causes Lafora progressive myoclonus epilepsy.";
RL Hum. Mutat. 23:170-176(2004).
RN [41]
RP VARIANT PRO-46.
RX PubMed=16021330; DOI=10.1007/s10038-005-0263-7;
RA Singh S., Suzuki T., Uchiyama A., Kumada S., Moriyama N., Hirose S.,
RA Takahashi Y., Sugie H., Mizoguchi K., Inoue Y., Kimura K., Sawaishi Y.,
RA Yamakawa K., Ganesh S.;
RT "Mutations in the NHLRC1 gene are the common cause for Lafora disease in
RT the Japanese population.";
RL J. Hum. Genet. 50:347-352(2005).
RN [42]
RP VARIANTS EPM2 ASN-140; TYR-148; LYS-210 AND TRP-310, CHARACTERIZATION OF
RP VARIANT EPM2 TRP-310, AND SUBCELLULAR LOCATION.
RX PubMed=18311786; DOI=10.1002/humu.20737;
RA Singh S., Satishchandra P., Shankar S.K., Ganesh S.;
RT "Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations
RT and their impact on subcellular localization of laforin and malin.";
RL Hum. Mutat. 29:E1-12(2008).
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. Shows strong phosphatase activity
CC towards complex carbohydrates in vitro, avoiding glycogen
CC hyperphosphorylation which is associated with reduced branching and
CC formation of insoluble aggregates (PubMed:16901901, PubMed:23922729,
CC PubMed:26231210, PubMed:25538239, PubMed:25544560). Dephosphorylates
CC phosphotyrosine and synthetic substrates, such as para-
CC nitrophenylphosphate (pNPP), and has low activity with phosphoserine
CC and phosphothreonine substrates (in vitro) (PubMed:11001928,
CC PubMed:11220751, PubMed:11739371, PubMed:14532330, PubMed:16971387,
CC PubMed:18617530, PubMed:22036712, PubMed:23922729, PubMed:14722920).
CC Has been shown to dephosphorylate MAPT (By similarity). Forms a complex
CC with 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
CC (PubMed:23922729). Also promotes proteasome-independent protein
CC degradation through the macroautophagy pathway (PubMed:20453062).
CC {ECO:0000250|UniProtKB:Q9WUA5, ECO:0000269|PubMed:11001928,
CC ECO:0000269|PubMed:11220751, ECO:0000269|PubMed:11739371,
CC ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:14722920,
CC ECO:0000269|PubMed:16901901, ECO:0000269|PubMed:16971387,
CC ECO:0000269|PubMed:18070875, ECO:0000269|PubMed:18617530,
CC ECO:0000269|PubMed:19036738, ECO:0000269|PubMed:20453062,
CC ECO:0000269|PubMed:22036712, ECO:0000269|PubMed:23624058,
CC ECO:0000269|PubMed:23922729, ECO:0000269|PubMed:25538239,
CC ECO:0000269|PubMed:25544560, ECO:0000269|PubMed:26231210}.
CC -!- FUNCTION: [Isoform 2]: Does not bind to glycogen (PubMed:18617530).
CC Lacks phosphatase activity and might function as a dominant-negative
CC regulator for the phosphatase activity of isoform 1 and isoform 7
CC (PubMed:18617530, PubMed:22036712). {ECO:0000269|PubMed:18617530,
CC ECO:0000269|PubMed:22036712}.
CC -!- FUNCTION: [Isoform 7]: Has phosphatase activity (in vitro).
CC {ECO:0000269|PubMed:22036712}.
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, ECO:0000269|PubMed:11001928,
CC ECO:0000269|PubMed:11220751};
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 Evidence={ECO:0000305|PubMed:11001928};
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 Evidence={ECO:0000305|PubMed:11001928};
CC -!- SUBUNIT: Homodimer (PubMed:16971387, PubMed:18617530, PubMed:23922729,
CC PubMed:25538239, PubMed:25544560). Interacts with itself
CC (PubMed:14532330). Interacts with PPP1R3B, PPP1R3C, PPP1R3D, HIRIP5,
CC and EPM2AIP1 (PubMed:12782127, PubMed:12915448, PubMed:14532330,
CC PubMed:16901901, PubMed:18070875). Binds glycogen and Lafora bodies
CC (PubMed:11739371, PubMed:14532330, PubMed:14706656, PubMed:15102711,
CC PubMed:18617530, PubMed:22036712). Interacts with NHLRC1/malin (via the
CC NHL repeats) (PubMed:15930137, PubMed:22036712, PubMed:23922729). Forms
CC a complex with NHLRC1/malin and HSP70 (PubMed:19036738). Interacts with
CC PPP1R3D; in the presence of NHLC1/malin the interaction leads to
CC ubiquitination and autophagic degradation of PPP1R3D. Interacts (via
CC the phosphatase domain) with MAPT/Tau; the interaction dephosphorylates
CC MAPT (PubMed:19542233). Isoform 1 and isoform 2 interact to form a
CC heterodimeric complex that lacks phosphatase activity (in vitro)
CC (PubMed:18617530). Active phosphatase isoform 7 and isoform 1 interact
CC with each other, but give rise to lower phosphatase activity than
CC isoform 1 or isoform 7 by themselves (in vitro) (PubMed:22036712).
CC Active phosphatase isoform 7 and inactive isoform 2 interact with each
CC other, but give rise to lower phosphatase activity than isoform 7 by
CC itself (in vitro) (PubMed:22036712). Interacts with PRDM8
CC (PubMed:22961547). {ECO:0000269|PubMed:11739371,
CC ECO:0000269|PubMed:12782127, ECO:0000269|PubMed:12915448,
CC ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:14706656,
CC ECO:0000269|PubMed:15102711, ECO:0000269|PubMed:15930137,
CC ECO:0000269|PubMed:16901901, ECO:0000269|PubMed:16971387,
CC ECO:0000269|PubMed:18070875, ECO:0000269|PubMed:18617530,
CC ECO:0000269|PubMed:19542233, ECO:0000269|PubMed:22036712,
CC ECO:0000269|PubMed:22961547, ECO:0000269|PubMed:23624058,
CC ECO:0000269|PubMed:23922729, ECO:0000269|PubMed:25538239,
CC ECO:0000269|PubMed:25544560}.
CC -!- INTERACTION:
CC O95278; Q6VVB1: NHLRC1; NbExp=7; IntAct=EBI-2506661, EBI-6426628;
CC O95278; Q9UQK1: PPP1R3C; NbExp=5; IntAct=EBI-2506661, EBI-2506727;
CC O95278-6; P06307: CCK; NbExp=3; IntAct=EBI-25836908, EBI-6624398;
CC O95278-6; P13473-2: LAMP2; NbExp=3; IntAct=EBI-25836908, EBI-21591415;
CC O95278-6; Q9Y371: SH3GLB1; NbExp=3; IntAct=EBI-25836908, EBI-2623095;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11001928,
CC ECO:0000269|PubMed:11220751, ECO:0000269|PubMed:11739371,
CC ECO:0000269|PubMed:15102711, ECO:0000269|PubMed:17908927}. Note=Under
CC glycogenolytic conditions localizes to the nucleus.
CC {ECO:0000269|PubMed:17908927}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC {ECO:0000269|PubMed:11001928, ECO:0000269|PubMed:11739371,
CC ECO:0000269|PubMed:11883934, ECO:0000269|PubMed:14532330,
CC ECO:0000269|PubMed:18311786, ECO:0000269|PubMed:18617530,
CC ECO:0000269|PubMed:22036712}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:11001928, ECO:0000269|PubMed:14722920,
CC ECO:0000269|PubMed:18311786}; Peripheral membrane protein
CC {ECO:0000269|PubMed:11001928, ECO:0000269|PubMed:18311786}; Cytoplasmic
CC side {ECO:0000269|PubMed:11001928, ECO:0000269|PubMed:18311786}. Cell
CC membrane {ECO:0000269|PubMed:11220751}. Note=Colocalizes with glycogen
CC synthase in punctate structures in the cytoplasm (PubMed:11739371,
CC PubMed:14532330). Primarily associated with polyribosomes at the rough
CC endoplasmic reticulum, and also detected at the plasma membrane
CC (PubMed:11001928, PubMed:11220751, PubMed:11883934, PubMed:18311786).
CC {ECO:0000269|PubMed:11001928, ECO:0000269|PubMed:11220751,
CC ECO:0000269|PubMed:11739371, ECO:0000269|PubMed:11883934,
CC ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:18311786}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm
CC {ECO:0000269|PubMed:18617530}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:11883934}; Peripheral membrane protein
CC {ECO:0000269|PubMed:11883934}; Cytoplasmic side
CC {ECO:0000269|PubMed:11883934}. Cell membrane
CC {ECO:0000269|PubMed:11883934}. Nucleus {ECO:0000269|PubMed:11883934,
CC ECO:0000269|PubMed:14722920, ECO:0000269|PubMed:18617530}. Note=Also
CC found in the nucleus. {ECO:0000269|PubMed:11883934,
CC ECO:0000269|PubMed:18617530}.
CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm
CC {ECO:0000269|PubMed:22036712}. Nucleus {ECO:0000269|PubMed:22036712}.
CC -!- SUBCELLULAR LOCATION: [Isoform 5]: Cytoplasm
CC {ECO:0000269|PubMed:22036712}. Nucleus {ECO:0000269|PubMed:22036712}.
CC -!- SUBCELLULAR LOCATION: [Isoform 7]: Cytoplasm
CC {ECO:0000269|PubMed:22036712}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=8;
CC Name=1; Synonyms=A, LDH1 {ECO:0000303|PubMed:11883934}, Laf331
CC {ECO:0000303|PubMed:22036712};
CC IsoId=O95278-1; Sequence=Displayed;
CC Name=2; Synonyms=B, C-terISO, Laf317 {ECO:0000303|PubMed:22036712};
CC IsoId=O95278-2; Sequence=VSP_011017, VSP_011018;
CC Name=4; Synonyms=Laf152 {ECO:0000303|PubMed:22036712};
CC IsoId=O95278-4; Sequence=VSP_011015, VSP_011016;
CC Name=5; Synonyms=Laf224 {ECO:0000303|PubMed:22036712};
CC IsoId=O95278-5; Sequence=VSP_042496, VSP_042497;
CC Name=6; Synonyms=Laf88 {ECO:0000303|PubMed:22036712};
CC IsoId=O95278-6; Sequence=VSP_042494;
CC Name=7; Synonyms=Laf177 {ECO:0000303|PubMed:22036712};
CC IsoId=O95278-7; Sequence=VSP_042495;
CC Name=8;
CC IsoId=O95278-8; Sequence=VSP_042493;
CC Name=9; Synonyms=POCR {ECO:0000303|PubMed:22036712};
CC IsoId=B3EWF7-1; Sequence=External;
CC -!- TISSUE SPECIFICITY: Expressed in heart, skeletal muscle, kidney,
CC pancreas and brain. Isoform 4 is also expressed in the placenta.
CC {ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:9771710}.
CC -!- DOMAIN: The CBM20 domain mediates binding to cytoplasmic glycogen and
CC to Lafora polyglucosan bodies. {ECO:0000269|PubMed:11739371,
CC ECO:0000269|PubMed:14706656}.
CC -!- PTM: Polyubiquitinated by NHLRC1/malin. {ECO:0000269|PubMed:15930137}.
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:0000269|PubMed:21728993}.
CC -!- DISEASE: Epilepsy, progressive myoclonic 2 (EPM2) [MIM:254780]: A form
CC of progressive myoclonic epilepsy, a clinically and genetically
CC heterogeneous group of disorders defined by the combination of action
CC and reflex myoclonus, other types of epileptic seizures, and
CC progressive neurodegeneration and neurocognitive impairment. EPM2 is an
CC autosomal recessive and severe form of adolescent-onset progressive
CC epilepsy. Typically, as seizures increase in frequency, cognitive
CC function declines towards dementia, and affected individuals die
CC usually within 10 years after onset. EPM2 occurs worldwide, but it is
CC particularly common in the mediterranean countries of southern Europe
CC and northern Africa, in southern India and in the Middle East. At the
CC cellular level, it is characterized by accumulation of starch-like
CC polyglucosans called Lafora bodies (LBs) that are most abundant in
CC organs with the highest glucose metabolism: brain, heart, liver and
CC skeletal muscle. Among other conditions involving polyglucosans, EPM2
CC is unique in that the inclusions are in neuronal dendrites but not
CC axons and the forming polyglucosan fibrils are associated with the
CC endoplasmic reticulum. {ECO:0000269|PubMed:11001928,
CC ECO:0000269|PubMed:11175283, ECO:0000269|PubMed:11739371,
CC ECO:0000269|PubMed:12019207, ECO:0000269|PubMed:12560877,
CC ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:14706656,
CC ECO:0000269|PubMed:14722920, ECO:0000269|PubMed:15009235,
CC ECO:0000269|PubMed:18311786, ECO:0000269|PubMed:25544560,
CC ECO:0000269|PubMed:26231210, ECO:0000269|PubMed:9771710,
CC ECO:0000269|PubMed:9931343}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative splicing.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: Produced by alternative splicing. May be
CC due to an intron retention. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 5]: Produced by alternative splicing.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 6]: Produced by alternative initiation at Met-
CC 244 of isoform 1. Transcript amplified but protein not detected.
CC {ECO:0000269|PubMed:22036712}.
CC -!- MISCELLANEOUS: [Isoform 7]: Produced by alternative splicing. Active
CC phosphatase. {ECO:0000269|PubMed:22036712}.
CC -!- MISCELLANEOUS: [Isoform 8]: Produced by alternative splicing.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAO15523.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};
CC Sequence=BAG51107.1; Type=Frameshift; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=The Lafora progressive myoclonus epilepsy mutation
CC and polymorphism database;
CC URL="http://projects.tcag.ca/lafora/";
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DR EMBL; AF084535; AAC83347.2; -; mRNA.
DR EMBL; AF284580; AAG18377.1; -; mRNA.
DR EMBL; AF454491; AAO15523.1; ALT_SEQ; mRNA.
DR EMBL; AF454492; AAO15524.1; -; mRNA.
DR EMBL; AF454493; AAO15525.1; -; mRNA.
DR EMBL; AF454494; AAO15526.1; -; mRNA.
DR EMBL; AK022721; BAG51107.1; ALT_FRAME; mRNA.
DR EMBL; AK299497; BAG61454.1; -; mRNA.
DR EMBL; AL023806; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL365193; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471051; EAW47844.1; -; Genomic_DNA.
DR EMBL; BC005286; AAH05286.1; -; mRNA.
DR EMBL; BC070047; AAH70047.1; -; mRNA.
DR EMBL; AJ130763; CAA10199.1; -; mRNA.
DR EMBL; AJ130764; CAA10200.1; -; mRNA.
DR CCDS; CCDS5206.1; -. [O95278-1]
DR CCDS; CCDS87452.1; -. [O95278-8]
DR CCDS; CCDS87453.1; -. [O95278-5]
DR CCDS; CCDS87454.1; -. [O95278-2]
DR RefSeq; NP_001018051.1; NM_001018041.1. [O95278-2]
DR RefSeq; NP_005661.1; NM_005670.3. [O95278-1]
DR RefSeq; XP_006715627.1; XM_006715564.3.
DR RefSeq; XP_011534418.1; XM_011536116.1. [O95278-8]
DR RefSeq; XP_016866789.1; XM_017011300.1.
DR RefSeq; XP_016866790.1; XM_017011301.1. [O95278-7]
DR RefSeq; XP_016866791.1; XM_017011302.1. [O95278-7]
DR PDB; 4R30; X-ray; 2.30 A; A/B/C/D=148-331.
DR PDB; 4RKK; X-ray; 2.40 A; A/C=1-329.
DR PDBsum; 4R30; -.
DR PDBsum; 4RKK; -.
DR AlphaFoldDB; O95278; -.
DR SMR; O95278; -.
DR BioGRID; 113679; 51.
DR IntAct; O95278; 9.
DR STRING; 9606.ENSP00000356489; -.
DR BindingDB; O95278; -.
DR ChEMBL; CHEMBL2311242; -.
DR CAZy; CBM20; Carbohydrate-Binding Module Family 20.
DR DEPOD; EPM2A; -.
DR iPTMnet; O95278; -.
DR PhosphoSitePlus; O95278; -.
DR BioMuta; EPM2A; -.
DR EPD; O95278; -.
DR MassIVE; O95278; -.
DR PaxDb; O95278; -.
DR PeptideAtlas; O95278; -.
DR PRIDE; O95278; -.
DR ProteomicsDB; 50779; -. [O95278-1]
DR ProteomicsDB; 50780; -. [O95278-2]
DR ProteomicsDB; 50782; -. [O95278-4]
DR ProteomicsDB; 50783; -. [O95278-5]
DR ProteomicsDB; 50784; -. [O95278-6]
DR ProteomicsDB; 50785; -. [O95278-7]
DR ProteomicsDB; 50786; -. [O95278-8]
DR ABCD; O95278; 1 sequenced antibody.
DR Antibodypedia; 19839; 527 antibodies from 38 providers.
DR DNASU; 7957; -.
DR Ensembl; ENST00000367519.9; ENSP00000356489.3; ENSG00000112425.16. [O95278-1]
DR Ensembl; ENST00000435470.2; ENSP00000405913.2; ENSG00000112425.16. [O95278-2]
DR Ensembl; ENST00000611340.5; ENSP00000480268.1; ENSG00000112425.16. [O95278-8]
DR Ensembl; ENST00000638262.1; ENSP00000492876.1; ENSG00000112425.16. [O95278-5]
DR Ensembl; ENST00000638778.1; ENSP00000491353.1; ENSG00000112425.16. [O95278-8]
DR Ensembl; ENST00000638783.1; ENSP00000491338.1; ENSG00000112425.16. [O95278-8]
DR Ensembl; ENST00000639423.1; ENSP00000492701.1; ENSG00000112425.16. [O95278-8]
DR Ensembl; ENST00000639465.1; ENSP00000491180.1; ENSG00000112425.16. [O95278-8]
DR GeneID; 7957; -.
DR KEGG; hsa:7957; -.
DR MANE-Select; ENST00000367519.9; ENSP00000356489.3; NM_005670.4; NP_005661.1.
DR UCSC; uc003qkw.4; human. [O95278-1]
DR CTD; 7957; -.
DR DisGeNET; 7957; -.
DR GeneCards; EPM2A; -.
DR GeneReviews; EPM2A; -.
DR HGNC; HGNC:3413; EPM2A.
DR HPA; ENSG00000112425; Tissue enhanced (skeletal muscle, tongue).
DR MalaCards; EPM2A; -.
DR MIM; 254780; phenotype.
DR MIM; 607566; gene.
DR neXtProt; NX_O95278; -.
DR OpenTargets; ENSG00000112425; -.
DR Orphanet; 501; Lafora disease.
DR PharmGKB; PA27832; -.
DR VEuPathDB; HostDB:ENSG00000112425; -.
DR eggNOG; KOG1716; Eukaryota.
DR GeneTree; ENSGT00390000010101; -.
DR HOGENOM; CLU_076792_0_0_1; -.
DR OMA; HLYKDCG; -.
DR OrthoDB; 865142at2759; -.
DR PhylomeDB; O95278; -.
DR TreeFam; TF332841; -.
DR BRENDA; 3.1.3.16; 2681.
DR PathwayCommons; O95278; -.
DR Reactome; R-HSA-3322077; Glycogen synthesis.
DR Reactome; R-HSA-3785653; Myoclonic epilepsy of Lafora.
DR SignaLink; O95278; -.
DR SIGNOR; O95278; -.
DR BioGRID-ORCS; 7957; 9 hits in 1076 CRISPR screens.
DR ChiTaRS; EPM2A; human.
DR GenomeRNAi; 7957; -.
DR Pharos; O95278; Tbio.
DR Proteomes; UP000005640; Chromosome 6.
DR Bgee; ENSG00000112425; Expressed in skeletal muscle tissue of rectus abdominis and 203 other tissues.
DR ExpressionAtlas; O95278; baseline and differential.
DR Genevisible; O95278; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0098556; C:cytoplasmic side of rough endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030246; F:carbohydrate binding; IDA:UniProtKB.
DR GO; GO:0019203; F:carbohydrate phosphatase activity; IDA:UniProtKB.
DR GO; GO:0004373; F:glycogen (starch) synthase activity; IEA:Ensembl.
DR GO; GO:2001069; F:glycogen binding; IDA:UniProtKB.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0016791; F:phosphatase activity; IDA:UniProtKB.
DR GO; GO:0046983; F:protein dimerization activity; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0008138; F:protein tyrosine/serine/threonine phosphatase activity; IEA:InterPro.
DR GO; GO:2001070; F:starch binding; IEA:Ensembl.
DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl.
DR GO; GO:0006816; P:calcium ion transport; IEA:Ensembl.
DR GO; GO:0046835; P:carbohydrate phosphorylation; IEA:Ensembl.
DR GO; GO:0016311; P:dephosphorylation; IDA:UniProtKB.
DR GO; GO:0014009; P:glial cell proliferation; IEA:Ensembl.
DR GO; GO:0005978; P:glycogen biosynthetic process; TAS:Reactome.
DR GO; GO:0005977; P:glycogen metabolic process; IMP:UniProtKB.
DR GO; GO:0046959; P:habituation; IEA:Ensembl.
DR GO; GO:0015813; P:L-glutamate transmembrane transport; IEA:Ensembl.
DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl.
DR GO; GO:0045786; P:negative regulation of cell cycle; IEA:Ensembl.
DR GO; GO:0035305; P:negative regulation of dephosphorylation; IDA:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; IEA:Ensembl.
DR GO; GO:0010923; P:negative regulation of phosphatase activity; IDA:UniProtKB.
DR GO; GO:0035335; P:peptidyl-tyrosine dephosphorylation; IMP:UniProtKB.
DR GO; GO:0046838; P:phosphorylated carbohydrate dephosphorylation; IDA:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IEA:Ensembl.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0006470; P:protein dephosphorylation; IDA:UniProtKB.
DR GO; GO:0001558; P:regulation of cell growth; IEA:Ensembl.
DR GO; GO:2000465; P:regulation of glycogen (starch) synthase activity; IEA:Ensembl.
DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IEA:Ensembl.
DR GO; GO:0042306; P:regulation of protein import into nucleus; IEA:Ensembl.
DR GO; GO:0045859; P:regulation of protein kinase activity; IEA:Ensembl.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; IEA:Ensembl.
DR GO; GO:0031396; P:regulation of protein ubiquitination; IEA:Ensembl.
DR GO; GO:1904666; P:regulation of ubiquitin protein ligase activity; IEA:Ensembl.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:Ensembl.
DR CDD; cd05806; CBM20_laforin; 1.
DR CDD; cd14526; DSP_laforin-like; 1.
DR DisProt; DP02647; -.
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 1: Evidence at protein level;
KW 3D-structure; Alternative initiation; Alternative splicing; Autophagy;
KW Carbohydrate metabolism; Cell membrane; Cytoplasm; Disease variant;
KW Endoplasmic reticulum; Epilepsy; Glycogen metabolism;
KW Glycogen storage disease; Hydrolase; Membrane; Neurodegeneration; Nucleus;
KW Phosphoprotein; Protein phosphatase; Reference proteome; Ubl conjugation.
FT CHAIN 1..331
FT /note="Laforin"
FT /id="PRO_0000094838"
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:0000305|PubMed:25544560,
FT ECO:0000305|PubMed:26231210"
FT ACT_SITE 266
FT /note="Phosphocysteine intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160,
FT ECO:0000305|PubMed:11220751, ECO:0000305|PubMed:11739371,
FT ECO:0000305|PubMed:14532330, ECO:0000305|PubMed:22036712,
FT ECO:0000305|PubMed:25538239, ECO:0000305|PubMed:25544560"
FT BINDING 32
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT BINDING 87
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT BINDING 103..107
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT BINDING 197
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT BINDING 235
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT BINDING 241
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT BINDING 267..272
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT BINDING 304
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:25544560,
FT ECO:0007744|PDB:4RKK"
FT SITE 329
FT /note="Required for homodimerization"
FT /evidence="ECO:0000269|PubMed:23922729"
FT MOD_RES 25
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:21728993"
FT VAR_SEQ 1..243
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_042494"
FT VAR_SEQ 1..159
FT /note="MRFRFGVVVPPAVAGARPELLVVGSRPELGRWEPRGAVRLRPAGTAAGDGAL
FT ALQEPGLWLGEVELAAEEAAQDGAEPGRVDTFWYKFLKREPGGELSWEGNGPHHDRCCT
FT YNENNLVDGVYCLPIGHWIEATGHTNEMKHTTDFYFNIAGHQAMHYSR -> MIFNK
FT (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042495"
FT VAR_SEQ 1..138
FT /note="Missing (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.4"
FT /id="VSP_042493"
FT VAR_SEQ 102..199
FT /note="NGPHHDRCCTYNENNLVDGVYCLPIGHWIEATGHTNEMKHTTDFYFNIAGHQ
FT AMHYSRILPNIWLGSCPRQVEHVTIKLKHELGITAVMNFQTEWDIV -> IASRRLPPA
FT QSGSSGPHPQPGPRPRAGPAGPGGARPGLFARVPAHSPGDLG (in isoform 4)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_011015"
FT VAR_SEQ 160..293
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_042496"
FT VAR_SEQ 200..331
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_011016"
FT VAR_SEQ 294..331
FT /note="YFLMAKRPAVYIDEEALARAQEDFFQKFGKVRSSVCSL -> PSTDAAPGGV
FT PAACAAGEGTHRVRALQRWGGPLHRGCLRLAPVCDGLESEEGAVFPHGQEAGCLH (in
FT isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_042497"
FT VAR_SEQ 310..320
FT /note="LARAQEDFFQK -> ASQDTFPL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9771710,
FT ECO:0000303|PubMed:9931343"
FT /id="VSP_011017"
FT VAR_SEQ 321..331
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9771710,
FT ECO:0000303|PubMed:9931343"
FT /id="VSP_011018"
FT VARIANT 25
FT /note="S -> P (in EPM2; atypical form; does not affect
FT glycogen binding)"
FT /evidence="ECO:0000269|PubMed:12019207,
FT ECO:0000269|PubMed:14706656"
FT /id="VAR_019465"
FT VARIANT 28
FT /note="E -> K (in EPM2; does not affect glycogen binding)"
FT /evidence="ECO:0000269|PubMed:14706656"
FT /id="VAR_019466"
FT VARIANT 32
FT /note="W -> G (in EPM2; impairs protein stability; affects
FT phosphatase activity; abolishes glycogen binding; abolishes
FT phosphatase activity with insoluble glucan; disrupts the
FT interaction with PPP1R3C; dbSNP:rs104893955)"
FT /evidence="ECO:0000269|PubMed:11739371,
FT ECO:0000269|PubMed:12019207, ECO:0000269|PubMed:14532330,
FT ECO:0000269|PubMed:14706656, ECO:0000269|PubMed:25544560,
FT ECO:0000269|PubMed:26231210"
FT /id="VAR_019467"
FT VARIANT 46
FT /note="A -> P (does not affect glycogen binding;
FT dbSNP:rs374338349)"
FT /evidence="ECO:0000269|PubMed:11735300,
FT ECO:0000269|PubMed:14706656, ECO:0000269|PubMed:16021330"
FT /id="VAR_019468"
FT VARIANT 84
FT /note="F -> L (in EPM2; affects phosphatase activity and
FT glycogen binding; disrupts the interaction with PPP1R3C;
FT dbSNP:rs1362231306)"
FT /evidence="ECO:0000269|PubMed:11175283,
FT ECO:0000269|PubMed:14532330"
FT /id="VAR_019469"
FT VARIANT 88
FT /note="F -> L (in EPM2; does not affect glycogen binding;
FT dbSNP:rs1034706422 and dbSNP:rs1463000703)"
FT /evidence="ECO:0000269|PubMed:14706656"
FT /id="VAR_019470"
FT VARIANT 91
FT /note="R -> P (in EPM2; atypical form; learning difficuties
FT with childhood-onset)"
FT /evidence="ECO:0000269|PubMed:14722920,
FT ECO:0000269|PubMed:15009235"
FT /id="VAR_019471"
FT VARIANT 108
FT /note="R -> C (in EPM2; loss of phosphatase activity;
FT reduced self-interaction capacity; disrupts the interaction
FT with PPP1R3C; dbSNP:rs137852915)"
FT /evidence="ECO:0000269|PubMed:12019207,
FT ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:9771710"
FT /id="VAR_019472"
FT VARIANT 114
FT /note="E -> D"
FT /evidence="ECO:0000269|PubMed:9771710"
FT /id="VAR_019473"
FT VARIANT 140
FT /note="K -> N (in EPM2)"
FT /evidence="ECO:0000269|PubMed:18311786"
FT /id="VAR_046383"
FT VARIANT 148
FT /note="N -> Y (in EPM2)"
FT /evidence="ECO:0000269|PubMed:18311786"
FT /id="VAR_046384"
FT VARIANT 171
FT /note="R -> H (in EPM2; results in ubiquitin-positive
FT perinuclear aggregates; no effect on glycogen binding;
FT abolishes phosphatase activity; may affect proper folding;
FT dbSNP:rs137852916)"
FT /evidence="ECO:0000269|PubMed:11001928,
FT ECO:0000269|PubMed:12019207, ECO:0000269|PubMed:14722920,
FT ECO:0000269|PubMed:25544560, ECO:0000269|PubMed:9931343"
FT /id="VAR_019474"
FT VARIANT 187
FT /note="T -> A (in EPM2; abolishes interaction with NHLRC1)"
FT /evidence="ECO:0000269|PubMed:12560877"
FT /id="VAR_019475"
FT VARIANT 194
FT /note="T -> I (in EPM2; results in ubiquitin-positive
FT perinuclear aggregates; loss of phosphatase activity;
FT affects glycogen binding; reduced self-interaction
FT capacity; abolishes interaction with NHLRC1, PPP1R3C and
FT PRKAA2; no effect on phosphorylation of protein;
FT dbSNP:rs375544596)"
FT /evidence="ECO:0000269|PubMed:12019207,
FT ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:9931343"
FT /id="VAR_019476"
FT VARIANT 210
FT /note="E -> K (in EPM2)"
FT /evidence="ECO:0000269|PubMed:18311786"
FT /id="VAR_046385"
FT VARIANT 240
FT /note="G -> S (in EPM2; impaired phosphatase activity; does
FT not affect glycogen binding; disrupts the interaction with
FT PPP1R3C)"
FT /evidence="ECO:0000269|PubMed:11175283,
FT ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:25544560"
FT /id="VAR_019477"
FT VARIANT 279
FT /note="G -> S (in EPM2; results in ubiquitin-positive
FT perinuclear aggregates; loss of phosphatase activity;
FT affects glycogen binding; disrupts the interaction with
FT PPP1R3C; dbSNP:rs137852917)"
FT /evidence="ECO:0000269|PubMed:12019207,
FT ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:14722920,
FT ECO:0000269|PubMed:9771710, ECO:0000269|PubMed:9931343"
FT /id="VAR_019478"
FT VARIANT 293
FT /note="Q -> L (in EPM2; results in ubiquitin-positive
FT perinuclear aggregates; may affect proper folding; loss of
FT phosphatase activity; affects glycogen binding; disrupts
FT the interaction with PPP1R3C; dbSNP:rs796052427)"
FT /evidence="ECO:0000269|PubMed:11001928,
FT ECO:0000269|PubMed:12019207, ECO:0000269|PubMed:14532330,
FT ECO:0000269|PubMed:9771710"
FT /id="VAR_019479"
FT VARIANT 294
FT /note="Y -> N (in EPM2; results in ubiquitin-positive
FT perinuclear aggregates; impairs phosphatase activity;
FT affects glycogen binding; disrupts the interaction with
FT PPP1R3C)"
FT /evidence="ECO:0000269|PubMed:12019207,
FT ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:25544560,
FT ECO:0000269|PubMed:9931343"
FT /id="VAR_019480"
FT VARIANT 301
FT /note="P -> L (in EPM2; impairs protein stability; impairs
FT phosphatase activity; affects glycogen binding; disrupts
FT the interaction with PPP1R3C; dbSNP:rs796052428)"
FT /evidence="ECO:0000269|PubMed:11175283,
FT ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:25544560"
FT /id="VAR_019481"
FT VARIANT 310
FT /note="L -> W (in EPM2; causes location of isoform 1 at
FT cytoplasmic punctae; does not affect homodimerization of
FT isoform 1 but prevents heterodimerization of isoform 1 and
FT isoform 2)"
FT /evidence="ECO:0000269|PubMed:18311786"
FT /id="VAR_046386"
FT MUTAGEN 8
FT /note="V->A: Loss of phosphatase activity. No effect on
FT glycogen binding."
FT /evidence="ECO:0000269|PubMed:25544560"
FT MUTAGEN 25
FT /note="S->A: Partial loss of phosphatase activity.
FT Abolishes homodimerization. Abolishes interaction with
FT NHLRC1, PPP1R3C and PRKAA2. Does not affect glycogen
FT binding. Reduces stability of the protein."
FT /evidence="ECO:0000269|PubMed:21728993"
FT MUTAGEN 25
FT /note="S->D: Partial loss of phosphatase activity.
FT Increases interaction with NHLRC1. Does not affect
FT interaction with NHLRC1, PPP1R3C or PRKAA2. Does not affect
FT binding to carbohydrate. Does not affect homodimerization."
FT /evidence="ECO:0000269|PubMed:21728993"
FT MUTAGEN 87
FT /note="K->A: Loss of phosphatase activity. Abolishes
FT glycogen binding."
FT /evidence="ECO:0000269|PubMed:11739371,
FT ECO:0000269|PubMed:25544560"
FT MUTAGEN 99
FT /note="W->A: Strongly reduces phosphatase activity.
FT Strongly reduces glycogen binding."
FT /evidence="ECO:0000269|PubMed:25544560"
FT MUTAGEN 109..110
FT /note="CC->SS: No effect on homodimerization or
FT carbohydrate binding. Decreased phosphatase activity."
FT /evidence="ECO:0000269|PubMed:23922729"
FT MUTAGEN 123
FT /note="C->S: No effect on homodimerization or carbohydrate
FT binding. Decreased phosphatase activity."
FT /evidence="ECO:0000269|PubMed:23922729"
FT MUTAGEN 126
FT /note="I->T: Strongly decreased phosphatase activity. No
FT effect on glycogen binding."
FT /evidence="ECO:0000269|PubMed:25544560"
FT MUTAGEN 142
FT /note="T->A: Strongly decreased phosphatase activity. No
FT effect on glycogen binding."
FT /evidence="ECO:0000269|PubMed:25544560"
FT MUTAGEN 168
FT /note="S->A,D: Abolishes interaction with NHLRC1."
FT /evidence="ECO:0000269|PubMed:21728993"
FT MUTAGEN 169
FT /note="C->S: No effect on homodimerization or carbohydrate
FT binding. Decreased phosphatase activity."
FT /evidence="ECO:0000269|PubMed:23922729"
FT MUTAGEN 169
FT /note="C->S: No effect on phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25538239"
FT MUTAGEN 171
FT /note="R->A: No effect on phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25538239"
FT MUTAGEN 187
FT /note="T->D: Abolishes interaction with NHLRC1."
FT /evidence="ECO:0000269|PubMed:21728993"
FT MUTAGEN 194
FT /note="T->D: Does not affect interaction with NHLRC1,
FT PPP1R3C or PRKAA2."
FT /evidence="ECO:0000269|PubMed:21728993"
FT MUTAGEN 197
FT /note="D->A: Strongly decreased phosphatase activity. No
FT effect on glycogen binding."
FT /evidence="ECO:0000269|PubMed:25538239,
FT ECO:0000269|PubMed:25544560"
FT MUTAGEN 205
FT /note="C->S: No effect on homodimerization or carbohydrate
FT binding. Decreased phosphatase activity."
FT /evidence="ECO:0000269|PubMed:23922729"
FT MUTAGEN 235
FT /note="D->A: Complete loss of phosphatase activity. Does
FT not affect glycogen binding."
FT /evidence="ECO:0000269|PubMed:14532330,
FT ECO:0000269|PubMed:25538239"
FT MUTAGEN 236
FT /note="M->A: Complete loss of phosphatase activity. No
FT effect on glycogen binding."
FT /evidence="ECO:0000269|PubMed:25544560"
FT MUTAGEN 250
FT /note="C->S: No effect on homodimerization or carbohydrate
FT binding. Decreased phosphatase activity."
FT /evidence="ECO:0000269|PubMed:23922729"
FT MUTAGEN 251
FT /note="L->A: Impairs protein stability. Strongly reduces
FT phosphatase activity. No effect on glycogen binding."
FT /evidence="ECO:0000269|PubMed:25544560"
FT MUTAGEN 266
FT /note="C->S: Complete loss of phosphatase activity. Does
FT not affect glycogen binding. Does not affect self-
FT interaction. Increases the interaction with PPP1R3C."
FT /evidence="ECO:0000269|PubMed:11220751,
FT ECO:0000269|PubMed:11739371, ECO:0000269|PubMed:14532330,
FT ECO:0000269|PubMed:22036712, ECO:0000269|PubMed:23922729,
FT ECO:0000269|PubMed:25538239, ECO:0000269|PubMed:25544560"
FT MUTAGEN 272
FT /note="R->A: Complete loss of phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25538239"
FT MUTAGEN 321
FT /note="F->S: Impairs protein stability. Strongly reduces
FT phosphatase activity. No effect on glycogen binding."
FT /evidence="ECO:0000269|PubMed:25544560"
FT MUTAGEN 329..331
FT /note="Missing: Fails to homodimerize. Does not affect
FT carbohydrate binding or phosphatase activity."
FT /evidence="ECO:0000269|PubMed:23922729"
FT MUTAGEN 329
FT /note="C->S: Fails to homodimerize. Does not affect
FT carbohydrate binding, interaction with NHLRC1, phosphatase
FT activity, or ubiquitination by NHLRC1."
FT /evidence="ECO:0000269|PubMed:23922729"
FT MUTAGEN 329
FT /note="C->S: No effect on homodimerization."
FT /evidence="ECO:0000269|PubMed:25538239"
FT CONFLICT 193
FT /note="Q -> K (in Ref. 8; AAH70047)"
FT /evidence="ECO:0000305"
FT CONFLICT 248
FT /note="A -> P (in Ref. 4; AAO15523)"
FT /evidence="ECO:0000305"
FT CONFLICT 258
FT /note="K -> E (in Ref. 5; BAG61454)"
FT /evidence="ECO:0000305"
FT CONFLICT 294
FT /note="Y -> H (in Ref. 5; BAG61454)"
FT /evidence="ECO:0000305"
FT STRAND 1..9
FT /evidence="ECO:0007829|PDB:4RKK"
FT HELIX 11..14
FT /evidence="ECO:0007829|PDB:4RKK"
FT STRAND 19..26
FT /evidence="ECO:0007829|PDB:4RKK"
FT HELIX 27..29
FT /evidence="ECO:0007829|PDB:4RKK"
FT TURN 30..32
FT /evidence="ECO:0007829|PDB:4RKK"
FT HELIX 34..36
FT /evidence="ECO:0007829|PDB:4RKK"
FT STRAND 58..67
FT /evidence="ECO:0007829|PDB:4RKK"
FT STRAND 84..91
FT /evidence="ECO:0007829|PDB:4RKK"
FT STRAND 97..103
FT /evidence="ECO:0007829|PDB:4RKK"
FT HELIX 104..106
FT /evidence="ECO:0007829|PDB:4RKK"
FT STRAND 108..110
FT /evidence="ECO:0007829|PDB:4RKK"
FT HELIX 114..116
FT /evidence="ECO:0007829|PDB:4RKK"
FT STRAND 121..123
FT /evidence="ECO:0007829|PDB:4RKK"
FT HELIX 138..151
FT /evidence="ECO:0007829|PDB:4RKK"
FT STRAND 157..161
FT /evidence="ECO:0007829|PDB:4R30"
FT STRAND 164..167
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 173..177
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 178..183
FT /evidence="ECO:0007829|PDB:4R30"
FT STRAND 188..191
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 195..201
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 203..205
FT /evidence="ECO:0007829|PDB:4R30"
FT STRAND 208..210
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 214..223
FT /evidence="ECO:0007829|PDB:4R30"
FT STRAND 227..230
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 238..258
FT /evidence="ECO:0007829|PDB:4R30"
FT STRAND 262..265
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 271..283
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 289..296
FT /evidence="ECO:0007829|PDB:4R30"
FT STRAND 303..305
FT /evidence="ECO:0007829|PDB:4R30"
FT HELIX 307..321
FT /evidence="ECO:0007829|PDB:4R30"
SQ SEQUENCE 331 AA; 37158 MW; DD79F917262AB458 CRC64;
MRFRFGVVVP PAVAGARPEL LVVGSRPELG RWEPRGAVRL RPAGTAAGDG ALALQEPGLW
LGEVELAAEE AAQDGAEPGR VDTFWYKFLK REPGGELSWE GNGPHHDRCC TYNENNLVDG
VYCLPIGHWI EATGHTNEMK HTTDFYFNIA GHQAMHYSRI LPNIWLGSCP RQVEHVTIKL
KHELGITAVM NFQTEWDIVQ NSSGCNRYPE PMTPDTMIKL YREEGLAYIW MPTPDMSTEG
RVQMLPQAVC LLHALLEKGH IVYVHCNAGV GRSTAAVCGW LQYVMGWNLR KVQYFLMAKR
PAVYIDEEAL ARAQEDFFQK FGKVRSSVCS L
