Defining the Tetramodular Dimer Structure of Laforin in Glycogen Metabolism and Lafora Disease

Abstract

Glycogen is the major form of carbohydrate storage in mammals and a dynamic participant in brain energetics. Slight aberrations in glycogen metabolism induce neuronal apoptosis; thus glycogen must be highly regulated. Lafora disease (LD) is a recessive neurodegenerative disorder that manifests as a single seizure during adolescence followed by progressive central nervous system degeneration and death within ten years. Mutations in the glycogen phosphatase laforin lead to the accumulation of neurotoxic, hyperphosphorylated glycogen known as Lafora bodies, which cause LD. Our lab recently determined the crystal structure of dimeric laforin. Using a variety of biochemical and biophysical methods including size exclusion chromatography, analytical ultracentrifugation, and small angle X‐ray scattering we have demonstrated that laforin exists as a dimer in solution. We have probed the effects of mechanistic and LD‐associated mutations using a yeast two‐hybrid system and various in vitro techniques, and we have demonstrated that laforin dimerization plays a unique and critical role in glycogen binding and dephosphorylation. This work begins to define the mutation‐specific mechanisms of LD and sheds new light on the regulation of glycogen metabolism.