Laforin,,a dual-specificity phosphatase involved in Lafora disease,is phosphorylated at Ser 25 by AMP-activated protein kinase

Carlos Romá-Mateo, Maria Del Carmen Solaz-Fuster, José Vicente Gimeno-Alcañiz, Vikas V. Dukhande, Jordi Donderis, Carolyn A. Worby, Alberto Marina, Olga Criado, Antonius Koller, Santiago Rodriguez De Cordoba, Matthew S. Gentry, Pascual Sanz

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in either the EPM2A gene, encoding the dual-specificity phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Previously, we and others showed that laforin and malin form a functional complex that regulates multiple aspects of glycogen metabolism, and that the interaction between laforin and malin is enhanced by conditions activating AMPK (AMP-activated protein kinase). In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser 25 as the residue involved in this modification. We also show that Ser 25 is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously established binding partners. The results of the present study suggest that phosphorylation of laforin-Ser 25 by AMPK provides a mechanism to modulate the interaction between laforin and malin. Regulation of this complex is necessary to maintain normal glycogen metabolism. Importantly, Ser 25 is mutated in some LD patients (S25P), and our results begin to elucidate the mechanism of disease in these patients.

Original languageEnglish
Pages (from-to)265-275
Number of pages11
JournalBiochemical Journal
Issue number2
StatePublished - Oct 15 2011


  • AMP-activated protein kinase (AMPK)
  • Alanine scanning mutagenesis
  • Glucan-phosphatase
  • Laforin
  • Phosphorylation
  • Protein-protein interaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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