Regulatory Role of One Critical Catalytic Loop of Polypeptide N-Acetyl-Galactosaminyltransferase-2 in Substrate Binding and Catalysis during Mucin-Type O-Glycosylation
Regulatory Role of One Critical Catalytic Loop of Polypeptide N-Acetyl-Galactosaminyltransferase-2 in Substrate Binding and Catalysis during Mucin-Type O-Glycosylation
复制标题
多肽 N-乙酰-半乳糖胺基转移酶-2 的一个关键催化环在粘蛋白型 O-糖基化过程中底物结合和催化中的调节作用
DOI：
10.1021/acscatal.9b03782
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发表时间：
2019
期刊：
影响因子：
12.9
通讯作者：
Lin-Tai Da
中科院分区：
文献类型：
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作者：
Jiaqi Tian;Feng Liu;Zhijue Xu;Jingjing Shi;Tao Liang;Yan Zhang;Lin-Tai Da
哺乳动物中主要的翻译后修饰之一是由多肽N-乙酰基半乳糖胺基转移酶(ppGalNAc-Ts)引发的粘蛋白型(GalNAc型)O-糖基化，其与许多生理和病理状况密切相关。然而，对 ppGalNAc-Ts 中一个关键催化环在底物结合时从开放状态到关闭状态的结构动力学的原子水平理解仍然难以实现。在这里，通过构建基于广泛的全原子分子动力学（MD）模拟的马尔可夫状态模型，总模拟时间约为20μs，我们在原子分辨率下揭示了ppGalNAc-T2中催化环在供体底物（UDP-GalNAc）结合后关闭/打开动力学过程中的关键亚稳态。整个催化环路闭合运动预计在约数十μs的时间尺度内发生，催化环路区域内的一些关键结构重排导致限速转变，再加上设计...
One of the dominant post-translational modifications in mammals is mucin-type (GalNAc-type) O-glycosylation initiated by polypeptide N-acetyl-galactosaminyltransferases (ppGalNAc-Ts), which is closely associated with many physiological and pathological conditions. An atomic-level understanding of the structural dynamics of one critical catalytic loop in ppGalNAc-Ts from an open to a closed state upon substrate binding, however, is still elusive. Here, by constructing a Markov state model based on extensive all-atom molecular dynamics (MD) simulations with an aggregated simulation time of ∼20 μs, we reveal, at atomistic resolution, the key metastable states of the catalytic loop in ppGalNAc-T2 during its closing/opening dynamics after donor substrate (UDP–GalNAc) binding. The overall catalytic-loop closing motion is estimated to take place at a timescale of ∼tens of μs, with the rate-limiting transition caused by some critical structural rearrangements within the catalytic loop region, coupled with the des...