title: Dimeric quaternary structure of human laforin.
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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Rajeshwer S
authors.initials: RS
authors.lastname: Sankhala
authors.affiliation: the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Adem C
authors.initials: AC
authors.lastname: Koksal
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Lan
authors.initials: L
authors.lastname: Ho
authors.affiliation: the Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and.
authors.forename: Felix
authors.initials: F
authors.lastname: Nitschke
authors.affiliation: 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.
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,. Electronic address: gino.cingolani@jefferson.edu.
authors.forename: Gino
authors.initials: G
authors.lastname: Cingolani
mesh_terms: D020134:Catalytic Domain; D006801:Humans; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human
keywords: Dual Specificity Phosphoprotein; Epilepsy; Glycogen; Lafora Disease; Laforin; Neurodegenerative Disease; Phosphatase; Phosphorylation