The Structure of Mammalian Prions and Their Aggregates.

Abstract

Prion diseases, such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (i.e., deer, elk, moose, and reindeer), and sheep scrapie, are caused by the misfolding of the cellular prion protein (PrPC) into a disease-causing conformer (PrPSc). PrPC is a normal, GPI-anchored protein that is expressed on the surface of neurons and other cell types. The structure of PrPC is well understood, based on studies of recombinant PrP, which closely mimics the structure of native PrPC. In contrast, PrPSc is prone to aggregate into a variety of quaternary structures, such as oligomers, amorphous aggregates, and amyloid fibrils. The propensity of PrPSc to assemble into these diverse forms of aggregates is also responsible for our limited knowledge about its structure. Then again, the repeating nature of certain regular PrPSc aggregates has allowed (lower resolution) insights into the structure of the infectious conformer, establishing a four-rung β-solenoid structure as a key element of its architecture.