A Unique Carbohydrate Binding Domain Targets the Lafora Disease Phosphatase to Glycogen

Wang, Jianyong; Stuckey, Jeanne A.; Wishart, Matthew J.; Dixon, Jack E.

doi:10.1074/jbc.c100686200

Cited by 154 publications

(171 citation statements)

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“…This prediction has proved true; the majority of EPM2A missense mutations found in LD patients result in a lack of phosphatase activity in vitro (FernandezSanchez et al 2003). Such an effect is not restricted to mutations located in the DSPD; loss of phosphatase activity was also shown for several CBD missense mutants (Wang et al 2002;Fernandez-Sanchez et al 2003).…”

Section: Epm2amentioning

confidence: 81%

“…Curiously, Lafora bodies are most commonly found in the organs with the highest glucose metabolism, namely brain, heart and liver, and all these tissues abundantly express laforin (Ganesh et al 2001b(Ganesh et al , 2002c. Indeed, it has been shown recently that the CBD of laforin targets the protein to glycogen and Lafora inclusion bodies in vitro, and LD mutations in laforin could affect such an affinity (Wang et al 2002;Ganesh et al 2004). Similar results were also observed when a substrate-trap mutant of laforin was overexpressed in a mouse model of LD (Chan et al 2004b).…”

Section: Disease Mechanismmentioning

confidence: 99%

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Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

et al. 2005

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Lafora's disease (LD) is an autosomal recessive and fatal form of progressive myoclonus epilepsy with onset in late childhood or adolescence. LD is characterised by the presence of intracellular polyglucosan inclusions, called Lafora bodies, in tissues including the brain, liver and skin. Patients have progressive neurologic deterioration, leading to death within 10 years of onset. No preventive or curative treatment is available for LD. At least three genes underlie LD, of which two have been isolated and mutations characterised: EPM2A and NHLRC1. The EPM2A gene product laforin is a protein phosphatase while the NHLRC1 gene product malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Analyses of the structure and function of these gene products suggest defects in posttranslational modification of proteins as the common mechanism that leads to the formation of Lafora inclusion bodies, neurodegeneration and the epileptic phenotype of LD. In this review, we summarise the available information on the genetic basis of LD, and correlate these advances with the rapidly expanding information about the mechanisms of LD gained from studies on both cell biological and animal models. Finally, we also discuss a possible mechanism to explain the locus heterogeneity observed in LD.

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Section: Epm2amentioning

confidence: 81%

Section: Disease Mechanismmentioning

confidence: 99%

Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

et al. 2005

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“…Laforin belongs to the dual-specificity protein phosphatase family and additionally contains a highly conserved polysaccharide binding domain. Laforin binds to glycogen (9,10), and virtually all of the laforin in a mouse skeletal muscle extract is recovered in the high-speed glycogen pellet (data not shown). Laforin is very sensitive to inhibition by polysaccharides, when assayed by using the generic phosphatase substrate p-nitrophenylphosphate (pNPP) (11).…”

mentioning

confidence: 94%

Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

Tagliabracci

Turnbull

Wang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

189

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Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. Lafora bodies, deposits of abnormally branched, insoluble glycogen-like polymers, form in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual-specificity protein phosphatase family that additionally contains a glycogen binding domain. The molecular basis for the formation of Lafora bodies is completely unknown. Glycogen, a branched polymer of glucose, contains a small amount of covalently linked phosphate whose origin and function are obscure. We report here that recombinant laforin is able to release this phosphate in vitro, in a time-dependent reaction with an apparent Km for glycogen of 4.5 mg/ml. Mutations of laforin that disable the glycogen binding domain also eliminate its ability to dephosphorylate glycogen. We have also analyzed glycogen from a mouse model of Lafora disease, Epm2a ؊/؊ mice, which develop Lafora bodies in several tissues. Glycogen isolated from these mice had a 40% increase in the covalent phosphate content in liver and a 4-fold elevation in muscle. We propose that excessive phosphorylation of glycogen leads to aberrant branching and Lafora body formation. This study provides a molecular link between an observed biochemical property of laforin and the phenotype of a mouse model of Lafora disease. The results also have important implications for glycogen metabolism generally.polyglucosan ͉ Lafora bodies ͉ Epm2a ͉ phosphate

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“…EPM2A, encodes a protein, laforin, that belongs to the dual specificity protein phosphatase family [9]. Laforin also contains a functional polysaccharide binding domain [10][11][12] that binds preferentially to polyglucosan over glycogen [13]. Some forty mutations have been identified throughout all four exons of the EPM2A gene (http://projects.tcag.ca/lafora/) [9,12,[14][15][16][17].…”

mentioning

confidence: 99%

“…Most mutations cause a loss of phosphatase activity in recombinant laforin [11,18]. However, one disease mutation, W32G, in the polysaccharide binding domain blocks glycogen binding [10,11,19] without completely destroying phosphatase activity [10,19]. Therefore, binding to polysaccharide is required for normal laforin function in vivo and one might speculate that laforin is somehow involved in glycogen metabolism.…”

mentioning

confidence: 99%

Glycogen metabolism in tissues from a mouse model of Lafora disease

Wang

Lohi

Skurat

et al. 2007

Archives of Biochemistry and Biophysics

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Laforin, encoded by the EPM2A gene, by sequence is a member of the dual specificity protein phosphatase family. Mutations in the EPM2A gene account for around half of the cases of Lafora disease, an autosomal recessive neurodegenerative disorder, characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of Lafora bodies, which contain polyglucosan, a poorly branched form of glycogen, in neurons, muscle and other tissues. Glycogen metabolizing enzymes were analyzed in a transgenic mouse over-expressing a dominant negative form of laforin that accumulates Lafora bodies in several tissues. Skeletal muscle glycogen was increased two-fold as was the total glycogen synthase protein. However, the −/+ glucose-6-P activity of glycogen synthase was decreased from 0.29 to 0.16. Branching enzyme activity was increased by 30%. Glycogen phosphorylase activity was unchanged. In whole brain, no differences in glycogen synthase or branching enzyme activities were found. Although there were significant differences in enzyme activities in muscle, the results do not support the hypothesis that Lafora body formation is caused by a major change in the balance between glycogen elongation and branching activities.Lafora disease is an autosomal recessive, progressive myoclonus epilepsy (OMIM #254780), with onset typically in teenagers followed by decline and death usually within ten years [1][2][3]. The disease is characterized by the presence of Lafora bodies, periodic acid-Schiff positive structures containing an abnormal form of glycogen, the branched polymer of glucose that serves as a stored form of glucose in many tissues. Although Lafora body formation in neurons is believed to account for the symptoms of the disease, the bodies are present in other tissues including liver, muscle and skin [4][5][6][7].Glycogen synthesis (Fig. 1) is mediated by glycogen synthase, which catalyzes formation of the predominant α-1,4-glycosidic linkage of the polymer and branching enzyme, which introduces the α-1,6-glycosidic branchpoints [8]. Degradation occurs in the cytosol through the action of glycogen phosphorylase and the debranching enzyme or alternatively in the lysosome via the activity of an α-glycosidase (acid maltase or GAA). In Lafora disease, a less ¶Correspondence to: Peter J. Roach, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122, Phone 317 274-1582, FAX 317 274-4686, E-mail proach@iupui.edu. 1 Present address: Department of Medicine, University of California, San Diego, USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal di...

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A Unique Carbohydrate Binding Domain Targets the Lafora Disease Phosphatase to Glycogen

Cited by 154 publications

References 27 publications

Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

Glycogen metabolism in tissues from a mouse model of Lafora disease

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