Structural Mechanism of Laforin Function in Glycogen Dephosphorylation and Lafora Disease

• Published in: Molecular cell Vol. 57; no. 2; pp. 261 - 272
• Main Authors: Raththagala, Madushi, Brewer, M. Kathryn, Parker, Matthew W., Sherwood, Amanda R., Wong, Brian K., Hsu, Simon, Bridges, Travis M., Paasch, Bradley C., Hellman, Lance M., Husodo, Satrio, Meekins, David A., Taylor, Adam O., Turner, Benjamin D., Auger, Kyle D., Dukhande, Vikas V., Chakravarthy, Srinivas, Sanz, Pascual, Woods, Virgil L., Li, Sheng, Vander Kooi, Craig W., Gentry, Matthew S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.01.2015
• Subjects: Catalytic Domain; Crystallography, X-Ray; Glycogen - metabolism; Humans; Lafora Disease - metabolism; Models, Molecular; Oligosaccharides - chemistry; Phosphates - chemistry; Phosphorylation; Protein Binding; Protein Multimerization; Protein Structure, Secondary; Protein Tyrosine Phosphatases, Non-Receptor - chemistry; Protein Tyrosine Phosphatases, Non-Receptor - physiology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2014.11.020

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. [Display omitted] •Determined the structure of laforin bound to glucan product to 2.4 Å•Used structure-guided mutagenesis to define the basis of glycogen dephosphorylation•Defined the structural mechanism of human Lafora disease mutations•Established architectural dynamics of wild-type and mutant laforin Raththagala et al. solve the structure of the glycogen phosphatase laforin and reveal insights into the mechanisms of Lafora disease, thereby connecting basic glycogen metabolism with human neurodegenerative disease.