Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: Implications for therapy

Rafael Alvarez, Jesús Casas, David J. López, Maitane Ibarguren, Ariadna Suari-Rivera, Silvia Terés, Francisca Guardiola-Serrano, Alexander Lossos, Xavier Busquets, Or Kakhlon*, Pablo V. Escribá

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca2+ and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD.

Original languageAmerican English
Pages (from-to)1598-1612
Number of pages15
JournalJournal of Lipid Research
Issue number8
StatePublished - 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.


  • Adult polyglucosan body disease
  • Diseases
  • Drug therapy
  • Membrane lipid therapy
  • Metabolic disease
  • Protein-membrane interactions
  • Triglycerides
  • Triheptanoin


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