The Structure of the Infectious Prion Protein and Its Propagation

Abstract

The prion diseases, which include Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids (i.e., deer, elk, moose, and reindeer), bovine spongiform encephalopathy in cattle, as well as sheep and goat scrapie, are caused by the conversion of the cellular prion protein (PrP^C) into a disease-causing conformer (PrP^Sc). PrP^C is a regular, GPI-anchored protein that is expressed on the cell surface of neurons and many other cell types. The structure of PrP^C is well studied, based on analyses of recombinant PrP, which is thought to mimic the structure of native PrP^C. The mature protein contains an N-terminal, unfolded domain and a C-terminal, globular domain that consists of three α-helices and only a small, two-stranded β-sheet. In contrast, PrP^Sc was found to contain predominantly β-structure and to aggregate into a variety of quaternary structures, such as oligomers, amorphous aggregates, amyloid fibrils, and two-dimensional crystals. The tendency of PrP^Sc to aggregate into these diverse forms is also responsible for our incomplete knowledge about its molecular structure. Nevertheless, the repeating nature of the more regular PrP^Sc aggregates has provided informative insights into the structure of the infectious conformer, albeit at limited resolution. These data established a four-rung β-solenoid architecture as the main element of its structure. Moreover, the four-rung β-solenoid architecture provides a molecular framework for an autocatalytic propagation mechanism, which could explain the conversion of PrP^C into PrP^Sc.

Keywords: Amyloid; Prion; Propagation; Protein misfolding; β-Solenoid.