Structural Mechanism of Laforin Function in Glycogen Dephosphorylation and Lafora Disease

Authors

Madushi Raththagala, University of KentuckyFollow
M. Kathryn Brewer, University of KentuckyFollow
Matthew W. Parker, University of KentuckyFollow
Amanda R. Sherwood, University of KentuckyFollow
Brian K. Wong, University of California, San Diego
Simon Hsu, University of California, San Diego
Travis M. Bridges, University of KentuckyFollow
Bradley C. Paasch, University of KentuckyFollow
Lance M. Hellman, University of Notre Dame
Satrio Husodo, University of KentuckyFollow
David A. Meekins, University of KentuckyFollow
Adam O. Taylor, University of Kentucky
Benjamin D. Turner, University of Kentucky
Kyle D. Auger, University of KentuckyFollow
Vikas V. Dukhande, University of KentuckyFollow
Srinivas Chakravarthy, Illinois Institute of Technology
Pascual Sanz, Instituto de Biomedicina de Valencia, Spain
Virgil L. Woods Jr., University of California, San Diego
Sheng Li, University of California, San Diego
Craig Vander Kooi, University of KentuckyFollow
Matthew S. Gentry, University of KentuckyFollow

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.

Document Type

Article

Publication Date

1-22-2015

Notes/Citation Information

Published in Molecular Cell, v. 57, no. 2, p. 261-272.

The document available for download is the authors' post-peer-review final draft of the article.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1016/j.molcel.2014.11.020

Repository Citation

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. Jr.; Li, Sheng; Vander Kooi, Craig; and Gentry, Matthew S., "Structural Mechanism of Laforin Function in Glycogen Dephosphorylation and Lafora Disease" (2015). Molecular and Cellular Biochemistry Faculty Publications. 49.
https://uknowledge.uky.edu/biochem_facpub/49