Abstract
PrPSc (scrapie isoform of the prion protein) prions are the infectious agent behind diseases such as Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (deer, elk, moose, and reindeer), as well as goat and sheep scrapie. PrPSc is an alternatively folded variant of the cellular prion protein, PrPC, which is a regular, GPI-anchored protein that is present on the cell surface of neurons and other cell types. While the structure of PrPC is well studied, the structure of PrPSc resisted high-resolution determination due to its general insolubility and propensity to aggregate. Cryo-electron microscopy, X-ray fiber diffraction, and a variety of other approaches defined the structure of PrPSc as a four-rung β-solenoid. A high-resolution structure of PrPSc still remains to be solved, but the four-rung β-solenoid architecture provides a molecular framework for the autocatalytic propagation mechanism that gives rise to the alternative conformation of PrPSc. Here, we summarize the current knowledge regarding the structure of PrPSc and speculate about the molecular conversion mechanisms that leads from PrPC to PrPSc.
Highlights
PrPSc was the first prion—i.e., infectious protein—to be discovered, and continues to be the quintessential prion, because of its historical preeminence, and because of its association with a unique class of fatal diseases
bovine spongiform encephalopathy (BSE) PrPSc prions transmitted to humans, causing transmissible variant Creutzfeldt–Jakob disease
While the cryo-electron microscopy data helped to decipher the overall architecture of PrPSc as a four-rung β-solenoid, the resolution was not sufficient to resolve the structure in atomic details
Summary
PrPSc was the first prion—i.e., infectious protein—to be discovered, and continues to be the quintessential prion, because of its historical preeminence, and because of its association with a unique class of fatal diseases. PrPSc is the only prion known to date to have caused local epidemic and epizootic outbursts. BSE PrPSc prions transmitted to humans, causing transmissible variant Creutzfeldt–Jakob disease (vCJD). At least three cases of transmission of vCJD PrPSc through blood transfusion have been documented [8] Another example of widespread infectious transmission of PrPSc prions is chronic wasting disease (CWD), which affects various cervid species and which is very contagious resulting in efficient horizontal transmission. PrPSc coerces PrPC , a glycosylphosphatidylinositol-anchored (GPI-anchored) membrane protein with the same primary but different secondary, tertiary, and quaternary structures, to adopt the PrPSc conformation This likely involves complete unfolding of PrPC , first, followed by refolding through a series of molecular events in which PrPSc acts as a physical template (vide infra). This mechanism provides hints to explain the strain and transmission barrier phenomena, crucial in the epidemiology and epizootiology of PrPSc
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