Preventing misfolding of the prion protein by trimethylamine N-oxide
Preventing misfolding of the prion protein by trimethylamine N-oxide
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DOI：
10.1021/bi0486379
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发表时间：
2004-10-19
期刊：
影响因子：
2.9
通讯作者：
Daggett, V
中科院分区：
文献类型：
--
作者：
Bennion, BJ;DeMarco, ML;Daggett, V
传染性海绵状脑病是一类与Pron蛋白相关的致命性神经退行性疾病。Prion蛋白通常以可溶的球状状态(PrPC)存在，似乎参与了中枢神经系统中的铜代谢和/或信号转导。感染或疾病发生时，另一种折叠形式的朊病毒蛋白(PrPSc)将可溶性的、主要是α-螺旋的PrPC转化为富含β-结构的聚集体。结构上无序的N-末端在低pH条件下转化为PrPSc时采用β-结构。化学伴侣，如三甲胺N-氧化物(TMAO)，可以防止在瘙痒病感染的小鼠神经母细胞瘤细胞中形成PrPSc[Tatzelt，J.，et al.(1996)EMBO J.15,6363-6373]。为了在原子水平上探索PrPC的TMAO保护机理，在有和没有1M TMAO的情况下，进行了分子动力学模拟。在低pH的PrPC模拟中，螺旋含量下降，N-末端进入小的天然β-折叠，产生类似PrPSc的状态。加入1 M TMAO导致旋转半径减小，蛋白质-蛋白质氢键数量增加，三级接触数量增加，这是由于N-末端形成Omega-Ioop并堆积在蛋白质的结构核心上，而不是像PrPC到PrPSc模拟那样增加延伸结构的水平。在1 M TMAO中开始的模拟中，N-末端发生了类似的结构重组，破坏了延伸的片层。TMAO的保护机制似乎是排他性的，与以前的理论和实验研究一致。TMAO诱导的N-末端构象变化阻止了在PrPC向PrPSc转化过程中重要的残基在低pH下呈现扩展的片层结构。
Transmissible spongiform encephalopathies are a class of fatal neurodegenerative diseases linked to the prion protein. The prion protein normally exists in a soluble, globular state (PrPC) that appears to participate in copper metabolism in the central nervous system and/or signal transduction. Infection or disease occurs when an alternatively folded form of the prion protein (PrPSc) converts soluble and predominantly alpha-helical PrPC into aggregates rich in beta-structure. The structurally disordered N-terminus adopts beta-structure upon conversion to PrPSc at low pH. Chemical chaperones, such as trimethylamine N-oxide (TMAO), can prevent formation of PrPSc in scrapie-infected mouse neuroblastoma cells [Tatzelt, J., et al. (1996) EMBO J. 15, 6363-6373]. To explore the mechanism of TMAO protection of PrPC at the atomic level, molecular dynamics simulations were performed under conditions normally leading to conversion (low pH) with and without 1 M TMAO. In PrPC simulations at low pH, the helix content drops and the N-terminus is brought into the small native beta-sheet, yielding a PrPSc-like state. Addition of 1 M TMAO leads to a decreased radius of gyration, a greater number of protein-protein hydrogen bonds, and a greater number of tertiary contacts due to the N-terminus forming an Omega-Ioop and packing against the structured core of the protein, not due to an increase in the level of extended structure as with the PrPC to PrPSc simulation. In simulations beginning with the "PrPSc-like" structure (derived from PrPC simulated at low pH in pure water) in 1 M TMAO, similar structural reorganization at the N-terminus occurred, disrupting the extended sheet. The mechanism of protection by TMAO appears to be exclusionary in nature, consistent with previous theoretical and experimental studies. The TMAO-induced N-terminal conformational change prevents residues that are important in the conversion of PrPC to PrPSc from assuming extended sheet structure at low pH.