Simulations of membrane-bound diglycosylated human prion protein reveal potential protective mechanisms against misfolding.
Simulations of membrane-bound diglycosylated human prion protein reveal potential protective mechanisms against misfolding.
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DOI：
10.1111/jnc.14044
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发表时间：
2017-07
影响因子：
4.7
通讯作者：
Daggett V
中科院分区：
文献类型：
--
作者：
Cheng CJ;Koldsø H;Van der Kamp MW;Schiøtt B;Daggett V
朊病毒疾病与朊病毒蛋白（PrP）从正常细胞形态（PrPC）到感染性痒病形态（PrPSc）的错误折叠有关。体内PrP的翻译后修饰可以在调节错误折叠过程中发挥重要作用。为了更深入地了解翻译后修饰对PrP结构和动力学的影响，并验证这种修饰可以与蛋白质相互作用的假设，我们通过糖磷脂酰肌醇锚点对二糖基化的人PrPC与脂质双分子层结合进行了分子动力学模拟。在三个不同的pH范围内进行了多次模拟，以探索pH对结构和动力学的影响。与纯蛋白PrPC的模拟相比，降低系统的pH值没有观察到大的影响。在所有的模拟中，蛋白质都向膜表面倾斜，并且假定的PrPSc寡聚化位点无法进入，从而提供了一种可能的保护机制，以防止PrPSc诱导的PrPC错误折叠。在分子动力学模拟中，与非糖基化蛋白相比，与脂质双分子层结合的二糖基化人类朊病毒蛋白PrPC在降低pH值时不会发生错误折叠，但蛋白质向膜表面倾斜，无法进入错误折叠和寡聚化的假定位点，从而提供了一种可能的防止错误折叠的保护机制。
Prion diseases are associated with the misfolding of the prion protein (PrP) from its normal cellular form (PrPC) to its infectious scrapie form (PrPSc). Posttranslational modifications of PrP in vivo can play an important role in modulating the process of misfolding. To gain more insight into the effects of posttranslational modifications on PrP structure and dynamics and to test the hypothesis that such modifications can interact with the protein, we have performed molecular dynamics simulations of diglycosylated human PrPC bound to a lipid bilayer via a glycophosphatidylinositol anchor. Multiple simulations were performed at three different pH ranges to explore pH effects on structure and dynamics. In contrast to simulations of protein-only PrPC, no large effects were observed upon lowering the pH of the system. The protein tilted toward the membrane surface in all of the simulations and the putative PrPSc oligomerization sites became inaccessible, thereby offering a possible protective mechanism against PrPSc-induced misfolding of PrPC. Diglycosylated human prion protein PrPC bound to a lipid bilayer did not misfold upon lowering the pH in molecular dynamics simulations, in contrast to the non-glycosylated protein in water, but the protein tilted toward the membrane surface and putative sites for misfolding and oligomerization became inaccessible, thereby offering a possible protective mechanism against misfolding.
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影响因子：
2.9
作者：
DeMarco, Mari L.;Silveira, Jay;Daggett, Valerie
通讯作者：
Daggett, Valerie
影响因子：
5.6
作者：
Leclerc, E;Peretz, D;Williamson, RA
通讯作者：
Williamson, RA
影响因子：
16.2
作者：
DeArmond, SJ;Sánchez, H;Prusiner, SB
通讯作者：
Prusiner, SB
DOI：
10.1073/pnas.0307178101
发表时间：
2004-02-24
影响因子：
11.1
作者：
DeMarco, ML;Daggett, V
通讯作者：
Daggett, V
影响因子：
2.9
作者：
Cheng, Hsin-Mei;Tsai, Tim W. T.;Chan, Jerry C. C.
通讯作者：
Chan, Jerry C. C.