Methionine Oxidation Perturbs the Structural Core of the Prion Protein and Suggests a Generic Misfolding Pathway*
Methionine Oxidation Perturbs the Structural Core of the Prion Protein and Suggests a Generic Misfolding Pathway*
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甲硫氨酸氧化扰乱朊病毒蛋白的结构核心并提示通用错误折叠途径*
DOI：
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发表时间：
2012
影响因子：
4.8
通讯作者：
J. H. Viles
中科院分区：
文献类型：
--
作者：
Nadine D. Younan;Rebecca C. Nadal;Paul Davies;David R. Brown;J. H. Viles
背景：氧化和蛋白质错误折叠是朊病毒疾病的基础。结果：氧化生成单体、螺旋和熔融球，随后是缺乏协同折叠的β构象。结论：朊病毒蛋白的氧化使其天然折叠不稳定，并与淀粉样纤维共享一个共同的错误折叠途径。意义：这种错误折叠可以解释羊瘙痒病分离株中高水平的氧化蛋氨酸。氧化应激和朊病毒蛋白（PrPC）的错误折叠是朊病毒疾病的基础。因此，我们探讨了氧化对PrPC的结构和稳定性的影响。尿素去折叠研究表明，H2 O2氧化降低了PrPC的热力学稳定性高达9 kJ/mol。1H-15 N NMR研究表明，甲硫氨酸氧化扰乱螺旋-C一面上的关键疏水残基如下：Met-205、瓦尔-209和Met-212以及残基瓦尔-160和Tyr-156。这些疏水残基聚集在一起，形成蛋白质的结构化核心，稳定其三元结构。铜催化氧化的PrPC导致更显着的改变的结构，产生单体熔融球物种，保留其天然的螺旋内容。进一步的铜催化氧化促进缺乏协同折叠的延伸的β链结构。这种从螺旋状熔融球到β-构象的转变与低pH下产生的错误折叠中间体具有惊人的相似性。因此，PrP可能与淀粉样蛋白纤维共享通用错误折叠途径，而不管促进错误折叠的条件如何。我们的观察结果支持这一假设，氧化的PrP不稳定的天然折叠的PrPC，促进过渡到PrPSc。这项研究给出了一个结构和热力学解释的高水平的氧化蛋氨酸在羊瘙痒病分离株。
Background: Oxidation and protein misfolding are fundamental to prion diseases. Results: Oxidation generates a monomeric, helical, and molten globule followed by a β-conformation that lacks a cooperative fold. Conclusion: Oxidation of the prion protein destabilizes its native fold and shares a common misfolding pathway to amyloid fibers. Significance: The misfolding may explain the high levels of oxidized methionine in scrapie isolates. Oxidative stress and misfolding of the prion protein (PrPC) are fundamental to prion diseases. We have therefore probed the effect of oxidation on the structure and stability of PrPC. Urea unfolding studies indicate that H2O2 oxidation reduces the thermodynamic stability of PrPC by as much as 9 kJ/mol. 1H-15N NMR studies indicate methionine oxidation perturbs key hydrophobic residues on one face of helix-C as follows: Met-205, Val-209, and Met-212 together with residues Val-160 and Tyr-156. These hydrophobic residues pack together and form the structured core of the protein, stabilizing its ternary structure. Copper-catalyzed oxidation of PrPC causes a more significant alteration of the structure, generating a monomeric molten globule species that retains its native helical content. Further copper-catalyzed oxidation promotes extended β-strand structures that lack a cooperative fold. This transition from the helical molten globule to β-conformation has striking similarities to a misfolding intermediate generated at low pH. PrP may therefore share a generic misfolding pathway to amyloid fibers, irrespective of the conditions promoting misfolding. Our observations support the hypothesis that oxidation of PrP destabilizes the native fold of PrPC, facilitating the transition to PrPSc. This study gives a structural and thermodynamic explanation for the high levels of oxidized methionine in scrapie isolates.
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影响因子：
3.9
作者：
Requena, JR;Dimitrova, MN;Levine, RL
通讯作者：
Levine, RL
影响因子：
2.9
作者：
Swietnicki, W;Morillas, M;Surewicz, WK
通讯作者：
Surewicz, WK
影响因子：
2.9
作者：
Nadal, Rebecca C.;Rigby, Stephen E. J.;Viles, John H.
通讯作者：
Viles, John H.
DOI：
10.1073/pnas.96.5.2042
发表时间：
1999-03
影响因子：
11.1
作者：
J. H. Viles;F. Cohen;S. Prusiner;D. Goodin;P. Wright;H. Dyson
通讯作者：
J. H. Viles;F. Cohen;S. Prusiner;D. Goodin;P. Wright;H. Dyson
影响因子：
2.9
作者：
STAHL, N;BALDWIN, MA;PRUSINER, SB
通讯作者：
PRUSINER, SB