title: Insights into Brain Glycogen Metabolism: THE STRUCTURE OF HUMAN BRAIN GLYCOGEN PHOSPHORYLASE.
abstract: Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glycogen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 Å) and in complex with its allosteric activator AMP (3.4 Å). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen.
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: the Fonction et Architecture des Assemblages Macromoléculaires, Institut de Biologie Intégrative de la Cellule, Université Paris Sud, UMR 9198 Orsay, 91405 France.
authors.forename: Ines
authors.initials: I
authors.lastname: Li de la Sierra-Gallay
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Duval
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Cocaign
authors.affiliation: the Université Paris Diderot, Sorbonne Paris Cité, Institut Jacques Monod, CNRS UMR 7592, 75013 Paris, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Léger
authors.affiliation: Thermo Fisher Scientific, Hemel Hempstead HP2 7GE, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Woffendin
authors.affiliation: the Université Paris Diderot, Sorbonne Paris Cité, Institut Jacques Monod, CNRS UMR 7592, 75013 Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Camadro
authors.affiliation: INSERM, UMR S1134, Université Paris Diderot, 75015 Paris, France, Université Paris Diderot, Sorbonne Paris Cité, 75004 Paris, France, Institut National de la Transfusion Sanguine, 75015 Paris, France, Laboratoire d'Excellence GR-Ex, 75015 Paris, France, UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France, and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Etchebest
authors.affiliation: the Institut Pasteur, Plateforme de Cristallographie, CNRS UMR 3528, 75015 Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France, UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France, and.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Dupret
authors.affiliation: From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France, UFR Sciences du Vivant, Université Paris Diderot, 75013 Paris, France, and fernando.rodrigues-lima@univ-paris-diderot.fr.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
mesh_terms: D000249:Adenosine Monophosphate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000494:Allosteric Regulation; D018360:Crystallography, X-Ray; D025002:Glycogen Phosphorylase, Brain Form / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020192:Lafora Disease / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains
chemical_list: D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000249:Adenosine Monophosphate; D025002:Glycogen Phosphorylase, Brain Form
keywords: Lafora disease (Lafora progressive myoclonic epilepsy, MELF); allosteric regulation; brain functions; brain metabolism; crystal structure; energy metabolism; glycogen; glycogen metabolism