Conformational plasticity of glycogenin and its maltosaccharide substrate during glycogen biogenesis
Conformational plasticity of glycogenin and its maltosaccharide substrate during glycogen biogenesis
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DOI：
10.1073/pnas.1113921108
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发表时间：
2011-12-27
影响因子：
11.1
通讯作者：
Yue, Wyatt W.
中科院分区：
文献类型：
--
作者：
Chaikuad, Apirat;Froese, D. Sean;Yue, Wyatt W.
糖原通过逐步葡糖基化反应启动与Tyr 195上自身共价连接的麦芽糖链的合成，引发糖原合成。我们已经捕获了人类糖原在其反应周期的晶体快照，揭示了由糖供体UDP-葡萄糖介导的基态和活性态之间的动态构象转换。这个开关包括一个多肽伸展含有Tyr 195的顺序，和一个约30个残基的“盖”部分覆盖的活性位点的主要运动。重排的盖子引导新生麦芽糖链以亚基内或亚基间模式进入活性位点，这取决于链长和空间因素，并定位供体和受体糖基用于催化。导致糖原累积病XV的Thr 83 Met突变在构象上锁定在基态并且无催化活性。我们的数据突出了糖原的构象可塑性和共存的两种模式的葡萄糖基化作为其催化机制的组成部分。
Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis. We have captured crystallographic snapshots of human glycogenin during its reaction cycle, revealing a dynamic conformational switch between ground and active states mediated by the sugar donor UDP-glucose. This switch includes the ordering of a polypeptide stretch containing Tyr195, and major movement of an approximately 30-residue "lid" segment covering the active site. The rearranged lid guides the nascent maltosaccharide chain into the active site in either an intra-or intersubunit mode dependent upon chain length and steric factors and positions the donor and acceptor sugar groups for catalysis. The Thr83Met mutation, which causes glycogen storage disease XV, is conformationally locked in the ground state and catalytically inactive. Our data highlight the conformational plasticity of glycogenin and coexistence of two modes of glucosylation as integral to its catalytic mechanism.