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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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Raththagala M,Brewer MK,Parker MW,Sherwood AR,Wong BK,Hsu S,Bridges TM,Paasch BC,Hellman LM,Husodo S,Meekins DA,Taylor AO,Turner BD,Auger KD,Dukhande VV,Chakravarthy S,Sanz P,Woods VL Jr,Li S,Vander Kooi CW,Gentry

doi

10.1016/j.molcel.2014.11.020

subject

Has Abstract

pub_date

2015-01-22 00:00:00

pages

261-72

issue

2

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(14)00915-0

journal_volume

57

pub_type

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