A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen.
Lafora disease (progressive myoclonus epilepsy of Lafora type) is an autosomal recessive neurodegenerative disorder resulting from defects in the EPM2A gene. EPM2A encodes a 331-amino acid protein containing a carboxyl-terminal phosphatase catalytic domain. We demonstrate that the EPM2A gene 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.
Wang
Jianyong
J
Life Sciences Institute and Department of Biological Chemistry, and the Biophysics Research Division, University of Michigan, Ann Arbor, Michigan 48109-0606, USA.
Stuckey
Jeanne A
JA
Wishart
Matthew J
MJ
Dixon
Jack E
JE
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D020134:Catalytic Domain; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015723:Gene Library; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D020192:Lafora Disease / Q000201:enzymology*; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics; D019636:Neurodegenerative Diseases; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D011994:Recombinant Proteins / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
D018076:DNA, Complementary; D011994:Recombinant Proteins; D006003:Glycogen; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human