Ser170 controls the conformational multiplicity of the loop 166-175 in prion proteins: implication for conversion and species barrier
Ser170 controls the conformational multiplicity of the loop 166-175 in prion proteins: implication for conversion and species barrier
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DOI：
10.1096/fj.07-8292com
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发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
Caflisch, Amedeo
中科院分区：
文献类型：
--
作者：
Gorfe, Alemayehu A.;Caflisch, Amedeo
细胞蛋白(PrPC)的自我永久化转化为聚集的富含β-折叠的构象与传染性海绵状脑病(TSE)有关。PrPC中的166-175(L1)环显示了物种间的序列和结构变化，被认为在物种屏障中发挥作用，特别是在防止TSE从宫颈传播到家畜和实验动物方面。L1在麋鹿PrP中以及在小鼠/麋鹿杂交中(其中小鼠的L1被麋鹿取代)中被订购，但在其他物种如小鼠、人类和牛中不被订购。为了研究L1动力学的来源和意义，我们对小鼠蛋白、小鼠/麋鹿杂交种进行了显式溶剂分子动力学模拟(总计约0.5MU S)，并进行了对照模拟，其中将小鼠序列重新引入到小鼠/麋鹿杂交种的结构中。我们发现L1的灵活性与Ser170的骨架动力学相关。此外，L1的迁移性促进了Tyr169的大量位移，Asp178-Tyr128和Asp178-Tyr169侧链氢键的断裂，以及Tyr169-Phe175 pi堆积作用的破坏。模拟结果超出了现有的实验数据，因为它们突出了这种相互作用网络对残基170和L1可塑性的依赖。
The self-perpetuating conversion of cellular prion proteins (PrPC) into an aggregated beta-sheet rich conformation is associated with transmissible spongiform encephalopathies (TSE). The loop 166 -175 (L1) in PrPC, which displays sequence and structural variation among species, has been suggested to play a role in species barrier, in particular against transmission of TSE from cervids to domestic and laboratory animals. L1 is ordered in elk PrP, as well as in a mouse/elk hybrid (in which L1 of mouse is replaced by elk) but not in other species such as mice, humans, and bovine. To investigate the source and significance of L1 dynamics, we carried out explicit solvent molecular dynamics simulations (approximate to 0.5 mu s in total) of the mouse prion protein, the mouse/elk hybrid, and control simulations, in which the mouse sequence is reintroduced into the structure of the mouse/elk hybrid. We found that the flexibility of L1 correlates with the backbone dynamics of Ser170. Furthermore, L1 mobility promotes a substantial displacement of Tyr169, rupture of the Asp178-Tyr128 and Asp178-Tyr169 side chain hydrogen bonds, as well as disruption of Tyr169-Phe175 pi-stacking interaction. The simulation results go beyond the available experimental data because they highlight the dependence of this network of interactions on residue 170 and L1 plasticity.