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J Biol Chem. 2015 Feb 20;290(8):4552-9. doi: 10.1074/jbc.M114.627406. Epub 2014 Dec 23.

Dimeric quaternary structure of human laforin.

Author information

1
From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
2
the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
3
the Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and.
4
the Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and the Institute of Medical Sciences, Department of Pediatrics, University of Toronto, Ontario M5S 1A8, Canada.
5
From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, gino.cingolani@jefferson.edu.

Abstract

The phosphatase laforin removes phosphate groups from glycogen during biosynthetic activity. Loss-of-function mutations in the gene encoding laforin is the predominant cause of Lafora disease, a fatal form of progressive myoclonic epilepsy. Here, we used hybrid structural methods to determine the molecular architecture of human laforin. We found that laforin adopts a dimeric quaternary structure, topologically similar to the prototypical dual specificity phosphatase VH1. The interface between the laforin carbohydrate-binding module and the dual specificity phosphatase domain generates an intimate substrate-binding crevice that allows for recognition and dephosphorylation of phosphomonoesters of glucose. We identify novel molecular determinants in the laforin active site that help decipher the mechanism of glucan phosphatase activity.

KEYWORDS:

Dual Specificity Phosphoprotein; Epilepsy; Glycogen; Lafora Disease; Laforin; Neurodegenerative Disease; Phosphatase; Phosphorylation

PMID:
25538239
PMCID:
PMC4335197
DOI:
10.1074/jbc.M114.627406
[Indexed for MEDLINE]
Free PMC Article

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