| Structural highlights
Disease
[EPM2A_HUMAN] Lafora disease. The disease is caused by mutations affecting the gene represented in this entry.
Function
[EPM2A_HUMAN] Has both dual-specificity protein phosphatase and glucan phosphatase activities. Together with the E3 ubiquitin ligase NHLRC1/malin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. Dephosphorylates phosphotyrosine, phosphoserine and phosphothreonine substrates in vitro. Has also been shown to dephosphorylate MAPT. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway. Isoform 2, an inactive phosphatase, could function as a dominant-negative regulator for the phosphatase activity of isoform 1.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
The phosphatase laforin removes phosphate groups from glycogen during biosynthetic activity. Loss of function mutations in the gene encoding laforin is the predominant cause of Lafora disease (LD), a fatal form of progressive myoclonic epilepsy. Here, we used hybrid structural methods to determine the molecular architecture of human laforin. We found that laforin adopts a dimeric quaternary structure, topologically similar to the prototypical dual specificity phosphatase (DSP) VH1. The interface between laforin carbohydrate-binding module (CBM) and DSP domain generates an intimate substrate-binding crevice that allows for recognition and dephosphorylation of phosphomonoesters of glucose. We identify novel molecular determinants in laforin active site that help decipher the mechanism of glucan phosphatase activity.
Dimeric quaternary structure of human laforin.,Sankhala RS, Koksal AC, Ho L, Nitschke F, Minassian BA, Cingolani G J Biol Chem. 2014 Dec 23. pii: jbc.M114.627406. PMID:25538239[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. PMID:11001928
- ↑ 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. PMID:11220751
- ↑ Worby CA, Gentry MS, Dixon JE. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. 2006 Oct 13;281(41):30412-8. Epub 2006 Aug 10. PMID:16901901 doi:http://dx.doi.org/10.1074/jbc.M606117200
- ↑ 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. PMID:18070875 doi:http://dx.doi.org/10.1074/jbc.M708712200
- ↑ Dubey D, Ganesh S. Modulation of functional properties of laforin phosphatase by alternative splicing reveals a novel mechanism for the EPM2A gene in Lafora progressive myoclonus epilepsy. Hum Mol Genet. 2008 Oct 1;17(19):3010-20. doi: 10.1093/hmg/ddn199. Epub 2008 Jul , 10. PMID:18617530 doi:http://dx.doi.org/10.1093/hmg/ddn199
- ↑ 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. PMID:19036738 doi:http://dx.doi.org/10.1093/hmg/ddn398
- ↑ Aguado C, Sarkar S, Korolchuk VI, Criado O, Vernia S, Boya P, Sanz P, de Cordoba SR, Knecht E, Rubinsztein DC. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum Mol Genet. 2010 Jul 15;19(14):2867-76. doi: 10.1093/hmg/ddq190. Epub 2010 May, 7. PMID:20453062 doi:http://dx.doi.org/10.1093/hmg/ddq190
- ↑ Rubio-Villena C, Garcia-Gimeno MA, Sanz P. Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex. Int J Biochem Cell Biol. 2013 Jul;45(7):1479-88. doi:, 10.1016/j.biocel.2013.04.019. Epub 2013 Apr 26. PMID:23624058 doi:http://dx.doi.org/10.1016/j.biocel.2013.04.019
- ↑ Sankhala RS, Koksal AC, Ho L, Nitschke F, Minassian BA, Cingolani G. Dimeric quaternary structure of human laforin. J Biol Chem. 2014 Dec 23. pii: jbc.M114.627406. PMID:25538239 doi:http://dx.doi.org/10.1074/jbc.M114.627406
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