Laforin

Definition:

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. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Dephosphorylates phosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity with phosphoserine and phosphothreonine substrates (in vitro). Has been shown to dephosphorylate MAPT (By similarity). 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]: Does not bind to glycogen. Lacks phosphatase activity and might function as a dominant-negative regulator for the phosphatase activity of isoform 1 and isoform 7.; [Isoform 7]: Has phosphatase activity (in vitro).

References:

[1]. Rajeshwer S Sankhala, et al. Dimeric quaternary structure of human laforin. J Biol Chem. 2015 Feb 20;290(8):4552-4559. [Content Brief]

[2]. Carmen Aguado, et al. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum Mol Genet. 2010 Jul 15;19(14):2867-76. [Content Brief]

[3]. B A Minassian, et al. Laforin is a cell membrane and endoplasmic reticulum-associated protein tyrosine phosphatase. Ann Neurol. 2001 Feb;49(2):271-5. [Content Brief]

[4]. Carolyn A Worby, et al. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. 2006 Oct 13;281(41):30412-8. [Content Brief]

[5]. David A Meekins, et al. Mechanistic Insights into Glucan Phosphatase Activity against Polyglucan Substrates. J Biol Chem. 2015 Sep 18;290(38):23361-70. [Content Brief]

[6]. Jianyong Wang, et al. A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen. J Biol Chem. 2002 Jan 25;277(4):2377-80. [Content Brief]

[7]. Madushi Raththagala, et al. Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease. Mol Cell. 2015 Jan 22;57(2):261-72. [Content Brief]

[8]. Pablo Sánchez-Martín, et al. Dimerization of the glucan phosphatase laforin requires the participation of cysteine 329. PLoS One. 2013 Jul 26;8(7):e69523. [Content Brief]

[9]. Carolyn A Worby, et al. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. 2008 Feb 15;283(7):4069-76. [Content Brief]

[10]. Leonarda Ianzano, et al. Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy. Hum Mutat. 2004 Feb;23(2):170-176. [Content Brief]

[11]. Deepti Dubey, et al. Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy. Genomics. 2012 Jan;99(1):36-43. [Content Brief]

[12]. Carla Rubio-Villena, et al. 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. [Content Brief]

[13]. Yan Liu, et al. Dimerization of Laforin is required for its optimal phosphatase activity, regulation of GSK3beta phosphorylation, and Wnt signaling. J Biol Chem. 2006 Nov 17;281(46):34768-74. [Content Brief]

[14]. S Ganesh, et al. 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. [Content Brief]

[15]. Punitee Garyali, et al. 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. [Content Brief]

[16]. Deepti Dubey, et al. 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. [Content Brief]

[17]. Maria Elena Fernández-Sánchez, et al. 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. [Content Brief]

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