Prion diseases are caused by the misfolding of prion protein (PrP). Misfolded PrP forms protease-resistant aggregates in vivo (PrP^Sc) that are able to template the conversion of the native form of the protein (PrP^C), a property shared by in vitro–produced PrP fibrils. Here we produced amyloid fibrils in vitro from recombinant, full-length human PrP^C (residues 23–231) and determined their structure using cryo-EM, building a model for the fibril core comprising residues 170−229. The PrP fibril consists of two protofibrils intertwined in a left-handed helix. Lys194 and Glu196 from opposing subunits form salt bridges, creating a hydrophilic cavity at the interface of the two protofibrils. By comparison with the structure of PrP^C, we propose that two α-helices in the C-terminal domain of PrP^C are converted into β-strands stabilized by a disulfide bond in the PrP fibril. Our data suggest that different PrP mutations may play distinct roles in modulating the conformational conversion.

on病毒疾病是由蛋白（PrP）的错误折叠引起的。错误折叠的PrP在体内形成蛋白酶抗性聚集体（PrP ^Sc），该聚集体能够模板化蛋白质天然形式（PrP ^C）的转化，这是体外生产的PrP原纤维共有的特性。在这里，我们从重组的全长人PrP ^C（残基23–231）中体外生产了淀粉样原纤维，并使用cryo-EM确定了它们的结构，从而建立了包含残基170-229的原纤维核心模型。PrP原纤维由两个缠绕在左手螺旋中的原纤维组成。来自相对的亚基的Lys194和Glu196形成盐桥，在两个原纤维的界面处形成一个亲水腔。与PrP ^C的结构比较，我们提出，PrP ^C的C末端结构域中的两个α螺旋被转化为通过PrP原纤维中的二硫键稳定的β链。我们的数据表明，不同的PrP突变可能在调节构象转化中发挥不同的作用。