Campbell Family Institute for Cancer Research, Department of Biochemistry, University of Toronto, Toronto Medical Discovery Tower 4-307, 101 College Street, Toronto, ON, Canada M5G 1L7.
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19808-13. doi: 10.1073/pnas.1005267107. Epub 2010 Nov 1.
Prion diseases occur when the normally α-helical prion protein (PrP) converts to a pathological β-structured state with prion infectivity (PrP(Sc)). Exposure to PrP(Sc) from other mammals can catalyze this conversion. Evidence from experimental and accidental transmission of prions suggests that mammals vary in their prion disease susceptibility: Hamsters and mice show relatively high susceptibility, whereas rabbits, horses, and dogs show low susceptibility. Using a novel approach to quantify conformational states of PrP by circular dichroism (CD), we find that prion susceptibility tracks with the intrinsic propensity of mammalian PrP to convert from the native, α-helical state to a cytotoxic β-structured state, which exists in a monomer-octamer equilibrium. It has been controversial whether β-structured monomers exist at acidic pH; sedimentation equilibrium and dual-wavelength CD evidence is presented for an equilibrium between a β-structured monomer and octamer in some acidic pH conditions. Our X-ray crystallographic structure of rabbit PrP has identified a key helix-capping motif implicated in the low prion disease susceptibility of rabbits. Removal of this capping motif increases the β-structure folding propensity of rabbit PrP to match that of PrP from mouse, a species more susceptible to prion disease.
朊病毒病是由于正常的α螺旋状朊病毒蛋白（PrP）转化为具有感染性的β结构状态（PrP（Sc））而引起的。暴露于来自其他哺乳动物的 PrP（Sc）可催化这种转化。来自实验和意外传播的朊病毒的证据表明，哺乳动物在朊病毒疾病易感性方面存在差异：仓鼠和小鼠表现出相对较高的易感性，而兔子、马和狗表现出较低的易感性。我们使用一种通过圆二色性（CD）定量测定 PrP 构象状态的新方法，发现朊病毒的易感性与哺乳动物 PrP 从天然的α螺旋状态转化为存在于单体-八聚体平衡中的细胞毒性β结构状态的固有倾向相关。关于β结构单体是否存在于酸性 pH 值下一直存在争议；沉降平衡和双波长 CD 证据表明，在某些酸性 pH 值条件下，β结构单体和八聚体之间存在平衡。我们的兔 PrP 的 X 射线晶体结构鉴定出一个关键的螺旋帽模体，该模体与兔子的低朊病毒疾病易感性有关。去除该帽模体增加了兔 PrP 的β结构折叠倾向，使其与更易患朊病毒疾病的小鼠 PrP 相匹配。
