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Official Full Name
epilepsy, progressive myoclonus type 2A, Lafora disease (laforin)

Recent Progress

Laforin is a human dual-specificity phosphatase (DSP) associated with glycogen metabolism regulation. Laforin contains a carbohydrate-binding module (CBM). Mutations in the gene coding for laforin can lead to the development of Lafora disease, which is a progressive fatal myoclonus epilepsy with early onset characterized by the intracellular deposition of Lafora bodies.

Researchers reported the crystal structure of laforin that is bound to phosphoglucan product, by presenting its unique integrated tertiary and quaternary structure. Through structure-guided mutagenesis along with biophysical and biochemical analyses, basis for normal function of laforin in glycogen metabolism were revealed. With analyses of LD(Lafora disease) patient mutations, the mechanism through which subsets of mutations disrupt laforin function was also defined.

The main cause of the Lafora disease is associated with the activity of two proteins, the phosphatase laforin with dual-specificity and the E3-ubiquitin ligase malin(Fig.1). Laforin can directly dephosphorylates glycogen. Recent report of a seires of laforin-binding partners in addition to malin indicated other roles of laforin than its catalytic activity. Further research has shown that the laforin malin complex is also related to other cellular processes, such as response to endoplasmic reticulum stress and misfolded protein clearance by the lysosomal pathway.

Fig. 1. A schematic of laforin and malin. LD mutations are shown for each protein, with missense mutations in red and other mutations in black. (A) Laforin contains a CBD and a DSP domain. (B) Malin contains a RING domain and six NHL repeats. (MS Gentry et al, 2005)

Hybrid structural methods were used by the investigators to determine the molecular architecture of human laforin. Data revealed that laforin presents a dimeric quaternary structure, which is topologically similar to the prototypical dual specificity phosphatase (DSP) VH1. An intimate substrate-binding crevice was produced from the interface between laforin carbohydrate-binding module (CBM) and DSP domain. This allows for recognition and de-phosphorylation of phosphor-monoesters of glucose. Novel molecular determinants in laforin active site were further determined. This discovery helped decipher the mechanism of glucan phosphatase activity.

Investigators have reported a thorough biophysical characterization of laforin-carbohydrate interaction through the use of soluble glycans. Researchers came to prove that glycans with higher order of polymerization have increased preference for laforin during interaction, the importance of tryptophan residues for glycan interaction was also confirmed. More intriguingly, results revealed that laforin-glycan interactions tend to occur with a favorable enthalpic contribution counter-balanced by an unfavourable entropic contribution. Further analysis displayed that the CBM-binding site can cover between 5 and 6 sugar units. This finding is consistent with the crystal structure of laforin. In order to determine the role of the phosphatase activity of laforin in the development of LD, investigators produced two Epm2a(-/-) mouse lines expressing either wild-type laforin or a mutant (C265S) laforin with only the lack of phosphatase activity. Findings from these models indicated that expression of either transgene could prevent formation of Lafora bodies and restores the impairment in macro-autophagy, thereby blocking the development of Lafora bodies in Epm2a(-/-) mice. These findings further confirmed that the pathogenic process of LD is the control of abnormal glycogen accumulation through intracellular proteolytic systems by the laforin malin complex, rather than glycogen dephosphorylation by laforin.

It has been proposed that the laforin malin complex play a role in the regulation of glycogen metabolism and protein quality control. Researchers assessed three arms of the protein degradation/ quality control process (the autophago-lysosomal pathway, the ubiquitin-proteasomal pathway, and the endoplasmic reticulum (ER) stress response) in mouse embryonic fibroblasts from Epm2a(-/-), Epm2b(-/-), and Epm2a(-/-) Epm2b(-/-) mice. According to the results, lack of malin (Epm2b(-/-) and Epm2a(-/-) Epm2b(-/-) cells) but not laforin (Epm2a(-/-) cells) decreased LAMP1 (a lysosomal marker). Thus it could be concluded that both laforin and malin knock-out cells display mTOR-dependent autophagy defects and decreased proteasomal activity without defects in the ER stress response. Researchers thus proposed that these defects may be secondary to glycogen overaccumulation. These findings also suggest a malin function independent of laforin, possibly in lysosomal biogenesis and/or lysosomal glycogen disposal.


  1. Gentry, Matthew S,, R. M. Carlos, and S. Pascual. "Laforin, a protein with many faces: glucan phosphatase, adapter protein, et alii. " Febs Journal 280.2(2013):525.
  2. Sankhala, R. S., et al. "Dimeric quaternary structure of human laforin. " Journal of Biological Chemistry 290.8(2015):4552-9.
  3. Dias, D. M., et al. "Biophysical characterization of laforin-carbohydrate interaction. " Biochemical Journal 473.3(2016):335-345.
  4. Raththagala, et al. "Structural Mechanism of Laforin Function in Glycogen Dephosphorylation and Lafora Disease." Molecular Cell 57.2(2015):261-72.
  5. Gayarre, J, et al. "The phosphatase activity of laforin is dispensable to rescue Epm2a-/- mice from Lafora disease. " Brain A Journal of Neurology 137.3(2014):806-18.
  6. Garyali, Punitee, et al. "Protein Degradation and Quality Control in Cells from Laforin and Malin Knockout Mice." Journal of Biological Chemistry 289.30(2014):20606-20614.