title: Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease.
abstract: Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Madushi
authors.initials: M
authors.lastname: Raththagala
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: M Kathryn
authors.initials: MK
authors.lastname: Brewer
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Parker
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Sherwood
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Wong
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Travis M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Paasch
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Lance M
authors.initials: LM
authors.lastname: Hellman
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Satrio
authors.initials: S
authors.lastname: Husodo
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Meekins
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Adam O
authors.initials: AO
authors.lastname: Taylor
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Turner
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Auger
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Vikas V
authors.initials: VV
authors.lastname: Dukhande
authors.affiliation: BioCAT, Illinois Institute of Technology, Chicago, IL 60616, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chakravarthy
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC and Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Valencia 46010, Spain.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Woods
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA. Electronic address: craig.vanderkooi@uky.edu.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Vander Kooi
authors.affiliation: Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA. Electronic address: matthew.gentry@uky.edu.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Gentry
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D020192:Lafora Disease / Q000378:metabolism*; D008958:Models, Molecular; D009844:Oligosaccharides / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry* / Q000502:physiology
chemical_list: D009844:Oligosaccharides; D010710:Phosphates; C016549:maltohexaose; D006003:Glycogen; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human