Premium
Lafora disease: Convergence of neurodegeneration with plant starch metabolism
Author(s) -
Gentry Matthew Shawn,
Vander Kooi Craig W.,
Taylor Adam O.,
Pace Rachel,
Meekins David A.,
Guo HouFu
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.954.1
Subject(s) - lafora disease , phosphatase , dual specificity phosphatase , biochemistry , neurodegeneration , phosphorylation , architecture domain , chemistry , microbiology and biotechnology , biology , disease , medicine , art , enterprise architecture management , architecture , visual arts , enterprise architecture
Reversible phosphorylation modulates many proteins involved in glycogenesis and glycogenolysis. Recent results from mammalian cells, mouse models, eukaryotic algae, and plants have identified a new phosphorylation target in glycogen metabolism, the glucan itself. Mutations in EPM2A lead to Lafora disease, a fatal neurodegenerative disease. EPM2A encodes laforin, a bimodular protein with an amino‐terminal carbohydrate binding module and a carboxy‐terminal dual specificity phosphatase domain. We recently demonstrated that laforin removes phosphate from phosphoglucans. S tarch E xcess 4 ( SEX4 ) encodes a similar phosphatase in plants, and we demonstrated that laforin and SEX4 are the founding members of the glucan phosphatases. Multiple groups have now shown that these phosphatases dephosphorylate phosphoglucans, but the physical basis for the function of laforin and SEX4 is unclear. We determined the crystal structure of SEX4, and found that it contains a phosphatase domain (DSP), carbohydrate binding module (CBM), and a previously unknown carboxy‐terminal domain. Hydrogen‐deuterium exchange mass spectrometry (DXMS) identified regions of the DSP domain that interact with glucans. Cumulatively, these results reveal the unique tertiary architecture of SEX4 that provides the physical basis for its function as a glucan phosphatase and present a model for the function of laforin.