Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease

Mol Cell. 2015 Jan 22;57(2):261-72. doi: 10.1016/j.molcel.2014.11.020.

Madushi Raththagala ¹, M Kathryn Brewer ¹, Matthew W Parker ¹, Amanda R Sherwood ¹, Brian K Wong ², Simon Hsu ², Travis M Bridges ¹, Bradley C Paasch ¹, Lance M Hellman ³, Satrio Husodo ¹, David A Meekins ¹, Adam O Taylor ¹, Benjamin D Turner ¹, Kyle D Auger ¹, Vikas V Dukhande ¹, Srinivas Chakravarthy ⁴, Pascual Sanz ⁵, Virgil L Woods Jr ², Sheng Li ², Craig W Vander Kooi ⁶, Matthew S Gentry ⁷

Affiliations

1 Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
2 Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
3 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
4 BioCAT, Illinois Institute of Technology, Chicago, IL 60616, USA.
5 Instituto de Biomedicina de Valencia, CSIC and Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Valencia 46010, Spain.
6 Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA. Electronic address: craig.vanderkooi@uky.edu.
7 Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA. Electronic address: matthew.gentry@uky.edu.

PMID: 25544560 DOI: 10.1016/j.molcel.2014.11.020

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.

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