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

• Published in: The Journal of biological chemistry Vol. 277; no. 4; pp. 2377 - 2380
• Main Authors: Wang, Jianyong, Stuckey, Jeanne A., Wishart, Matthew J., Dixon, Jack E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2002; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Blotting, Western; Catalytic Domain; Cell Line; COS Cells; Cytoplasm - metabolism; DNA, Complementary - metabolism; EPM2A gene; Gene Library; glycogen; Glycogen - metabolism; glycogen synthase; Humans; Lafora disease; Lafora Disease - enzymology; Microscopy, Fluorescence; Models, Molecular; Molecular Sequence Data; Muscles - metabolism; Mutation; Myoclonic Epilepsies, Progressive - genetics; Neurodegenerative Diseases; phosphatase; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - metabolism; Plasmids - metabolism; Precipitin Tests; Protein Structure, Tertiary; Protein Tyrosine Phosphatases - chemistry; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases, Non-Receptor; Recombinant Proteins - metabolism; Tissue Distribution; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C100686200

Lafora disease (progressive myoclonus epilepsy of Lafora type) is an autosomal recessive neurodegenerative disorder resulting from defects in the EPM2A gene. EPM2Aencodes a 331-amino acid protein containing a carboxyl-terminal phosphatase catalytic domain. We demonstrate that the EPM2Agene product also contains an amino-terminal carbohydrate binding domain (CBD) and that the CBD is critical for association with glycogen both in vitro and in vivo. The CBD domain localizes the phosphatase to specific subcellular compartments that correspond to the expression pattern of glycogen processing enzyme, glycogen synthase. Mutations in the CBD result in mis-localization of the phosphatase and thereby suggest that the CBD targets laforin to intracellular glycogen particles where it is likely to function. Thus naturally occurring mutations within the CBD of laforin likely result in progressive myoclonus epilepsy due to mis-localization of phosphatase expression.