Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations.
Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations.
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糖原脱支酶的晶体结构及其催化和致病突变的见解
DOI：
10.1038/ncomms11229
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发表时间：
2016-04-18
影响因子：
16.6
通讯作者：
Xiang S
中科院分区：
文献类型：
--
作者：
Zhai L;Feng L;Xia L;Yin H;Xiang S
糖原是一种支链葡萄糖聚合物，是重要的能量储存。它的去支化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GDE缺陷与统称为糖原累积病III型（GSDIII）的严重疾病有关。我们报告晶体结构的GDE和它的复合物与寡糖，和结构指导的诱变和生化研究，以评估结构的观察。这些研究揭示了GDE中不同的结构域催化糖原脱支中的顺序反应、其催化机制和高度特异性的底物识别。GDE独特的三级结构提供了额外的接触，糖原除了其活性位点，我们的生化实验表明，他们介导的招聘糖原和调节其活动。结合对GDE催化的理解及其致病突变的功能表征，提供了对GSDIII的分子见解。
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.