Grants and Contracts Details
Mutations in laforin, a dual specificity phosphatase (DSP) with a carbohydrate binding domain (CBM) that dephosphorylates glycogen, cause Lafora disease (LD). We recently determined the structure of the laforin dimer bound to a phosphoglucan to a resolution of 2.4A. Our crystal structure and preliminary data suggest that the laforin binds long and branched glucan chains characteristic of its endogenous substrate glycogen. The first Aim of this proposal is to determine the role of laforin dimerization for its function. A controversy exists about the nature of the laforin dimer interface. I will use a variety of techniques to resolve this controversy, investigate the effect of LD mutations at the dimer interface, and define how dimerization facilitates cooperative binding of carbohydrate substrates. The second Aim of this proposal is to establish the role of the CBM-DSP interface in maintaining specificity of laforin for site-specific dephosphorylation of glucose residues in glycogen. We have developed a variety of assays to explore the dynamics and effect of mutations in this region. These investigations are critical for understanding the precise mechanisms by which laforin regulates glycogen phosphorylation, shedding light on the metabolic regulation of glycogen and the molecular basis of LD.
|Effective start/end date||7/1/16 → 6/30/17|
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