Dimeric quaternary structure of human laforin

J Biol Chem. 2015 Feb 20;290(8):4552-9. doi: 10.1074/jbc.M114.627406. Epub 2014 Dec 23.

Abstract

The phosphatase laforin removes phosphate groups from glycogen during biosynthetic activity. Loss-of-function mutations in the gene encoding laforin is the predominant cause of Lafora disease, a fatal form of progressive myoclonic epilepsy. Here, we used hybrid structural methods to determine the molecular architecture of human laforin. We found that laforin adopts a dimeric quaternary structure, topologically similar to the prototypical dual specificity phosphatase VH1. The interface between the laforin carbohydrate-binding module and the dual specificity phosphatase domain generates an intimate substrate-binding crevice that allows for recognition and dephosphorylation of phosphomonoesters of glucose. We identify novel molecular determinants in the laforin active site that help decipher the mechanism of glucan phosphatase activity.

Keywords: Dual Specificity Phosphoprotein; Epilepsy; Glycogen; Lafora Disease; Laforin; Neurodegenerative Disease; Phosphatase; Phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Humans
  • Protein Multimerization*
  • Protein Structure, Quaternary
  • Protein Tyrosine Phosphatases, Non-Receptor / chemistry*
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism
  • Structure-Activity Relationship

Substances

  • Protein Tyrosine Phosphatases, Non-Receptor
  • EPM2A protein, human

Associated data

  • PDB/4R30