Canmetcon
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Identification
HMDB Protein ID HMDBP01891
Secondary Accession Numbers
  • 7291
Name Laforin
Synonyms
  1. LAFPTPase
  2. Lafora PTPase
Gene Name EPM2A
Protein Type Enzyme
Biological Properties
General Function Involved in carbohydrate binding
Specific Function Dual specificity protein phosphatase. May be involved in the control of glycogen metabolism, particularly in monitoring for and preventing the formation of poorly branched glycogen molecules (polyglucosans). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Forms a complex with NHLRC1/malin and HSP70 and this complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Isoform 2, an inactive phosphatase, could function as a dominant-negative regulator for the phosphatase activity of isoform 1.
Pathways Not Available
Reactions
Protein tyrosine phosphate + Water → protein tyrosine + Phosphoric acid details
A phosphoprotein + Water → a protein + Phosphoric acid details
GO Classification
Biological Process
glycogen metabolic process
nervous system development
behavior
Cellular Component
cytosol
endoplasmic reticulum
plasma membrane
nucleus
polysome
Function
phosphoprotein phosphatase activity
protein tyrosine phosphatase activity
hydrolase activity, acting on ester bonds
binding
catalytic activity
hydrolase activity
phosphoric ester hydrolase activity
phosphatase activity
protein tyrosine/serine/threonine phosphatase activity
carbohydrate binding
Molecular Function
protein tyrosine/serine/threonine phosphatase activity
protein serine/threonine phosphatase activity
starch binding
protein tyrosine phosphatase activity
Process
phosphorus metabolic process
phosphate metabolic process
dephosphorylation
protein amino acid dephosphorylation
metabolic process
primary metabolic process
carbohydrate metabolic process
cellular metabolic process
Cellular Location
  1. Cell membrane
  2. Nucleus
  3. Isoform 2:Endoplasmic reticulum
Gene Properties
Chromosome Location 6
Locus 6q24
SNPs EPM2A
Gene Sequence
>996 bp
ATGCGCTTCCGCTTTGGGGTGGTGGTGCCACCCGCCGTGGCCGGCGCCCGGCCGGAGCTG
CTGGTGGTGGGGTCGCGGCCCGAGCTGGGGCGTTGGGAGCCGCGCGGTGCCGTCCGCCTG
AGGCCGGCCGGCACCGCGGCGGGCGACGGGGCCCTGGCGCTGCAGGAGCCGGGCCTGTGG
CTCGGGGAGGTGGAGCTGGCGGCCGAGGAGGCGGCGCAGGACGGGGCGGAGCCGGGCCGC
GTGGACACGTTCTGGTACAAGTTCCTGAAGCGGGAGCCGGGAGGAGAGCTCTCCTGGGAA
GGCAATGGACCTCATCATGACCGTTGCTGTACTTACAATGAAAACAACTTGGTGGATGGT
GTGTATTGTCTCCCAATAGGACACTGGATTGAGGCCACTGGGCACACCAATGAAATGAAG
CACACAACAGACTTCTATTTTAATATTGCAGGCCACCAAGCCATGCATTATTCAAGAATT
CTACCAAATATCTGGCTGGGTAGCTGCCCTCGTCAGGTGGAACATGTAACCATCAAACTG
AAGCATGAATTGGGGATTACAGCTGTAATGAATTTCCAGACTGAATGGGATATTGTACAG
AATTCCTCAGGCTGTAACCGCTACCCAGAGCCCATGACTCCAGACACTATGATTAAACTA
TATAGGGAAGAAGGCTTGGCCTACATCTGGATGCCAACACCAGATATGAGCACCGAAGGC
CGAGTACAGATGCTGCCCCAGGCGGTGTGCCTGCTGCATGCGCTGCTGGAGAAGGGACAC
ATCGTGTACGTGCACTGCAACGCTGGGGTGGGCCGCTCCACCGCGGCTGTCTGCGGCTGG
CTCCAGTATGTGATGGGCTGGAATCTGAGGAAGGTGCAGTATTTCCTCATGGCCAAGAGG
CCGGCTGTCTACATTGACGAAGAGGCCTTGGCCCGGGCACAAGAAGATTTTTTCCAGAAA
TTTGGGAAGGTTCGTTCTTCTGTGTGTAGCCTGTAG
Protein Properties
Number of Residues 331
Molecular Weight 35518.41
Theoretical pI 6.265
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>Laforin
MRFRFGVVVPPAVAGARPELLVVGSRPELGRWEPRGAVRLRPAGTAAGDGALALQEPGLW
LGEVELAAEEAAQDGAEPGRVDTFWYKFLKREPGGELSWEGNGPHHDRCCTYNENNLVDG
VYCLPIGHWIEATGHTNEMKHTTDFYFNIAGHQAMHYSRILPNIWLGSCPRQVEHVTIKL
KHELGITAVMNFQTEWDIVQNSSGCNRYPEPMTPDTMIKLYREEGLAYIWMPTPDMSTEG
RVQMLPQAVCLLHALLEKGHIVYVHCNAGVGRSTAAVCGWLQYVMGWNLRKVQYFLMAKR
PAVYIDEEALARAQEDFFQKFGKVRSSVCSL
GenBank ID Protein 6005986
UniProtKB/Swiss-Prot ID O95278
UniProtKB/Swiss-Prot Entry Name EPM2A_HUMAN
PDB IDs Not Available
GenBank Gene ID AF084535
GeneCard ID EPM2A
GenAtlas ID EPM2A
HGNC ID HGNC:3413
References
General References
  1. Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L, Jones MC, Horton R, Hunt SE, Scott CE, Gilbert JG, Clamp ME, Bethel G, Milne S, Ainscough R, Almeida JP, Ambrose KD, Andrews TD, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beare DM, Beasley H, Beasley O, Bird CP, Blakey S, Bray-Allen S, Brook J, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Clark SY, Clark G, Clee CM, Clegg S, Cobley V, Collier RE, Collins JE, Colman LK, Corby NR, Coville GJ, Culley KM, Dhami P, Davies J, Dunn M, Earthrowl ME, Ellington AE, Evans KA, Faulkner L, Francis MD, Frankish A, Frankland J, French L, Garner P, Garnett J, Ghori MJ, Gilby LM, Gillson CJ, Glithero RJ, Grafham DV, Grant M, Gribble S, Griffiths C, Griffiths M, Hall R, Halls KS, Hammond S, Harley JL, Hart EA, Heath PD, Heathcott R, Holmes SJ, Howden PJ, Howe KL, Howell GR, Huckle E, Humphray SJ, Humphries MD, Hunt AR, Johnson CM, Joy AA, Kay M, Keenan SJ, Kimberley AM, King A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd CR, Lloyd DM, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, Maslen GL, Matthews L, McCann OT, McLaren SJ, McLay K, McMurray A, Moore MJ, Mullikin JC, Niblett D, Nickerson T, Novik KL, Oliver K, Overton-Larty EK, Parker A, Patel R, Pearce AV, Peck AI, Phillimore B, Phillips S, Plumb RW, Porter KM, Ramsey Y, Ranby SA, Rice CM, Ross MT, Searle SM, Sehra HK, Sheridan E, Skuce CD, Smith S, Smith M, Spraggon L, Squares SL, Steward CA, Sycamore N, Tamlyn-Hall G, Tester J, Theaker AJ, Thomas DW, Thorpe A, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, White SS, Whitehead SL, Whittaker H, Wild A, Willey DJ, Wilmer TE, Wood JM, Wray PW, Wyatt JC, Young L, Younger RM, Bentley DR, Coulson A, Durbin R, Hubbard T, Sulston JE, Dunham I, Rogers J, Beck S: The DNA sequence and analysis of human chromosome 6. Nature. 2003 Oct 23;425(6960):805-11. [PubMed:14574404 ]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  3. Cheng A, Zhang M, Gentry MS, Worby CA, Dixon JE, Saltiel AR: A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease. Genes Dev. 2007 Oct 1;21(19):2399-409. [PubMed:17908927 ]
  4. Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ, Dunham I, Gardner R, Fong CY, Carpenter S, Jardim L, Satishchandra P, Andermann E, Snead OC 3rd, Lopes-Cendes I, Tsui LC, Delgado-Escueta AV, Rouleau GA, Scherer SW: Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet. 1998 Oct;20(2):171-4. [PubMed:9771710 ]
  5. Ganesh S, Agarwala KL, Ueda K, Akagi T, Shoda K, Usui T, Hashikawa T, Osada H, Delgado-Escueta AV, Yamakawa K: Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Hum Mol Genet. 2000 Sep 22;9(15):2251-61. [PubMed:11001928 ]
  6. Serratosa JM, Gomez-Garre P, Gallardo ME, Anta B, de Bernabe DB, Lindhout D, Augustijn PB, Tassinari CA, Malafosse RM, Topcu M, Grid D, Dravet C, Berkovic SF, de Cordoba SR: A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Hum Mol Genet. 1999 Feb;8(2):345-52. [PubMed:9931343 ]
  7. Minassian BA, Andrade DM, Ianzano L, Young EJ, Chan E, Ackerley CA, Scherer SW: Laforin is a cell membrane and endoplasmic reticulum-associated protein tyrosine phosphatase. Ann Neurol. 2001 Feb;49(2):271-5. [PubMed:11220751 ]
  8. Ganesh S, Suzuki T, Yamakawa K: Alternative splicing modulates subcellular localization of laforin. Biochem Biophys Res Commun. 2002 Mar 15;291(5):1134-7. [PubMed:11883934 ]
  9. Wang J, Stuckey JA, Wishart MJ, Dixon JE: A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen. J Biol Chem. 2002 Jan 25;277(4):2377-80. Epub 2001 Dec 5. [PubMed:11739371 ]
  10. Ianzano L, Zhao XC, Minassian BA, Scherer SW: Identification of a novel protein interacting with laforin, the EPM2a progressive myoclonus epilepsy gene product. Genomics. 2003 Jun;81(6):579-87. [PubMed:12782127 ]
  11. Ganesh S, Tsurutani N, Suzuki T, Ueda K, Agarwala KL, Osada H, Delgado-Escueta AV, Yamakawa K: The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain. Hum Mol Genet. 2003 Sep 15;12(18):2359-68. Epub 2003 Jul 29. [PubMed:12915448 ]
  12. Fernandez-Sanchez ME, Criado-Garcia O, Heath KE, Garcia-Fojeda B, Medrano-Fernandez I, Gomez-Garre P, Sanz P, Serratosa JM, Rodriguez de Cordoba S: Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Hum Mol Genet. 2003 Dec 1;12(23):3161-71. Epub 2003 Oct 7. [PubMed:14532330 ]
  13. Ganesh S, Tsurutani N, Suzuki T, Hoshii Y, Ishihara T, Delgado-Escueta AV, Yamakawa K: The carbohydrate-binding domain of Lafora disease protein targets Lafora polyglucosan bodies. Biochem Biophys Res Commun. 2004 Jan 23;313(4):1101-9. [PubMed:14706656 ]
  14. Gentry MS, Worby CA, Dixon JE: Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8501-6. Epub 2005 Jun 1. [PubMed:15930137 ]
  15. Worby CA, Gentry MS, Dixon JE: Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. 2008 Feb 15;283(7):4069-76. Epub 2007 Dec 10. [PubMed:18070875 ]
  16. Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, Parihar R, Ganesh S: The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet. 2009 Feb 15;18(4):688-700. doi: 10.1093/hmg/ddn398. Epub 2008 Nov 25. [PubMed:19036738 ]
  17. Gomez-Garre P, Sanz Y, Rodriguez De Cordoba SR, Serratosa JM: Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Eur J Hum Genet. 2000 Dec;8(12):946-54. [PubMed:11175283 ]
  18. Ganesh S, Shoda K, Amano K, Uchiyama A, Kumada S, Moriyama N, Hirose S, Yamakawa K: Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene. Mol Cell Probes. 2001 Oct;15(5):281-9. [PubMed:11735300 ]
  19. Ganesh S, Delgado-Escueta AV, Suzuki T, Francheschetti S, Riggio C, Avanzini G, Rabinowicz A, Bohlega S, Bailey J, Alonso ME, Rasmussen A, Thomson AE, Ochoa A, Prado AJ, Medina MT, Yamakawa K: Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. Hum Mol Genet. 2002 May 15;11(11):1263-71. [PubMed:12019207 ]
  20. Ki CS, Kong SY, Seo DW, Hong SB, Kim HJ, Kim JW: Two novel mutations in the EPM2A gene in a Korean patient with Lafora's progressive myoclonus epilepsy. J Hum Genet. 2003;48(1):51-4. [PubMed:12560877 ]
  21. Annesi G, Sofia V, Gambardella A, Candiano IC, Spadafora P, Annesi F, Cutuli N, De Marco EV, Civitelli D, Carrideo S, Tarantino P, Barone R, Zappia M, Quattrone A: A novel exon 1 mutation in a patient with atypical lafora progressive myoclonus epilepsy seen as childhood-onset cognitive deficit. Epilepsia. 2004 Mar;45(3):294-5. [PubMed:15009235 ]
  22. Ianzano L, Young EJ, Zhao XC, Chan EM, Rodriguez MT, Torrado MV, Scherer SW, Minassian BA: Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy. Hum Mutat. 2004 Feb;23(2):170-6. [PubMed:14722920 ]
  23. Singh S, Suzuki T, Uchiyama A, Kumada S, Moriyama N, Hirose S, Takahashi Y, Sugie H, Mizoguchi K, Inoue Y, Kimura K, Sawaishi Y, Yamakawa K, Ganesh S: Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population. J Hum Genet. 2005;50(7):347-52. Epub 2005 Jul 15. [PubMed:16021330 ]
  24. Singh S, Satishchandra P, Shankar SK, Ganesh S: Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations and their impact on subcellular localization of laforin and malin. Hum Mutat. 2008 Jun;29(6):E1-12. doi: 10.1002/humu.20737. [PubMed:18311786 ]