Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.

中文翻译：

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糖原解支酶的晶体结构及其催化作用和致病突变的见解。

糖原是一种支链的葡萄糖聚合物，并起着重要的储能作用。它的分支是其动员的关键步骤。在动物和真菌中，170 kDa糖原脱支酶（GDE）催化该反应。人类中的GDE缺乏症与严重疾病相关联，这些疾病被统称为III型糖原贮积病（GSDIII）。我们报告了GDE的晶体结构及其与寡糖的复合物，以及结构指导的诱变和生化研究以评估结构观察结果。这些研究表明，GDE中不同的结构域催化糖原解支化中的顺序反应，其催化机理和高度特异性的底物识别。GDE独特的三级结构除其活性位点外，还提供了与糖原的其他接触，我们的生化实验表明，它们介导了糖原的募集并调节其活性。结合对GDE催化的理解及其引起疾病的突变的功能特性，可提供对GSDIII的分子认识。