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.
|Number of pages||12|
|State||Published - Jan 22 2015|
Bibliographical noteFunding Information:
We thank Drs. Mike Begley, Carolyn Worby, Skip Waechter, Carlos Roma-Mateo, Pablo Sanchez-Martin, and Yvonne Fondufe-Mittendorf for assistance and advice, as well as Drs. Carol Beach, Jing Chen, and Martin Chow of the UK COBRE Center for Molecular Medicine Proteomics and Protein Analytical Core. This study was supported by NIH Grants R01NS070899 (M.S.G.), P20GM103486 (M.S.G. and C.W.V.K), R01AI081982 (S.L. and V.L.W.), R01GM020501 (S.L. and V.L.W.), TL1RR033172 (A.R.S.), P41GM103622 (S.C.), DE-AC02-06CH11357 (Advanced Photon Source), and R01AI101436 (S.L. and V.L.W); KSEF Grants KSEF-2268-RDE-014 and KSEF-2971-RDE-017 (M.S.G.); Mizutani Foundation for Glycoscience Award (M.S.G.); NSF Grant IIA-1355438 (M.S.G.); University of Notre Dame Office of Research (L.M.H.); and SAF2011-27442 grant from the Spanish Ministry of Economy (P.S.). M.S.G. and C.W.V.K. are founders of OptiMol Enzymes LLC.
© 2015 Elsevier Inc.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology