Mathieu Cécile, Li de la Sierra-Gallay Ines, Duval Romain, Xu Ximing, Cocaign Angélique, Léger Thibaut, Woffendin Gary, Camadro Jean-Michel, Etchebest Catherine, Haouz Ahmed, Dupret Jean-Marie, Rodrigues-Lima Fernando
From the Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013 Paris, France.
the Fonction et Architecture des Assemblages Macromoléculaires, Institut de Biologie Intégrative de la Cellule, Université Paris Sud, UMR 9198 Orsay, 91405 France.
J Biol Chem. 2016 Aug 26;291(35):18072-83. doi: 10.1074/jbc.M116.738898. Epub 2016 Jul 8.
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.
脑糖原代谢在学习或记忆巩固等主要脑功能中起着关键作用。然而，正如在拉福拉病中所观察到的，脑内糖原代谢的改变和糖原积累会导致神经退行性变。糖原磷酸化酶（GP）是糖原代谢中的关键酶，催化糖原动员的限速步骤。此外，三种GP同工酶（肌肉型、肝脏型和脑型）通过代谢物和磷酸化进行变构调节，以响应激素信号，从而微调糖原分解以满足能量和代谢需求。尽管肌肉型和肝脏型GP的结构已为人所知数十年，但脑型GP（bGP）的结构尽管在脑糖原代谢中起关键作用，却一直难以捉摸。在此，我们报告了与聚乙二醇400（2.5 Å）结合以及与其变构激活剂AMP（3.4 Å）结合的人bGP的晶体结构。这些结构表明，bGP与肌肉型GP具有更紧密的结构关系，肌肉型GP也被AMP激活，这与肝脏型GP不同，肝脏型GP不被AMP激活。重要的是，尽管人bGP与其他两种哺乳动物同工酶在结构上有相似之处，但bGP的结构揭示了脑同工酶特有的分子特征，这为深入理解变构效应剂AMP对这些变构酶激活特性的差异提供了帮助。总体而言，我们的研究进一步支持了GP同工酶独特的结构和调节特性有助于肌肉、肝脏和脑糖原发挥不同功能。
