Prion Protein Structure and Its Role in Disease
An examination of how a prion protein's change in physical conformation, not its sequence, is the fundamental event driving its transformation into a pathogen.
Prion proteins are a unique class of proteins that can exist in two distinct structural forms. One is a normal, cellular protein found in healthy organisms, while the other is a misfolded, infectious agent responsible for a group of fatal neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). These diseases include Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep. Unlike viruses or bacteria, prions are composed solely of protein, lacking any genetic material like DNA or RNA.
The difference between the harmless and disease-causing protein lies not in their amino acid sequence, but in their three-dimensional shape. The normal protein can be induced to misfold into the infectious shape upon contact with the pathogenic form. This structural transformation is the central event in prion disease, leading to a cascade of misfolding that results in brain damage and the characteristic “spongy” appearance of affected tissue.
Architecture of the Cellular Prion Protein (PrPC)
The cellular prion protein (PrPC) is a glycoprotein on the surface of cells, particularly neurons in the central nervous system. Its structure has two main domains. The C-terminal half of the protein forms a stable, globular domain with a high content of alpha-helices and two short, anti-parallel beta-sheets. This structured region is stabilized by a disulfide bond that helps maintain its three-dimensional shape.
The N-terminal half of PrPC is largely flexible and lacks a defined structure, containing a distinctive segment of octapeptide repeats. The protein also has sites for N-linked glycosylation, the attachment of complex sugar molecules. PrPC is tethered to the outer cell membrane by a glycosylphosphatidylinositol (GPI) anchor, which secures its C-terminus to the cell surface.
The Misfolded Prion Protein (PrPSc) Conformation
The transition from PrPC to the pathogenic PrPSc isoform involves a dramatic rearrangement of its secondary structure. This change primarily affects the C-terminal globular domain, where alpha-helical structures refold into a high proportion of beta-sheets. This structural alteration is the defining characteristic of the infectious prion.
This transformation imparts damaging properties to the protein. A primary one is its partial resistance to proteases, which are enzymes that normally break down old or damaged proteins. The newly formed beta-sheet core is highly stable and resists degradation, which contributes to the accumulation of PrPSc in the brain. The high beta-sheet content also causes the protein to aggregate into large, insoluble clumps known as amyloid plaques. These aggregates disrupt brain tissue, leading to the neuronal cell death and spongiform changes of prion diseases.
The Structural Transition: How PrPC Converts to PrPSc
The conversion of PrPC into PrPSc is a post-translational event, occurring after the protein is synthesized. The process does not involve any change to the protein’s amino acid sequence, but is a change in folding. This event is triggered by an interaction between the normal protein and a pre-existing PrPSc molecule.
Two primary models have been proposed to explain this change. The “template-assisted” model suggests an incoming PrPSc molecule acts as a template. It binds to a PrPC molecule and forces it to refold into the pathogenic, beta-sheet-rich shape, creating a new PrPSc molecule that continues the chain reaction.
Another concept is the “nucleated polymerization” model. This model posits that while PrPC can convert to PrPSc, the change only becomes stable when several PrPSc molecules form a seed. Once a seed exists, it rapidly recruits and converts more PrPC, causing the aggregate to grow exponentially. This process explains the long incubation periods of prion diseases, as the initial seed formation may be a slow event.
Structural Determinants of Prion Behavior
Subtle structural differences in PrPSc aggregates give rise to different prion “strains.” Similar to viral strains, these can have distinct biological properties like incubation times and clinical symptoms, even if from the same host protein. This strain variation is determined by the precise way beta-sheets are arranged in the PrPSc aggregate. Different conformations replicate with varying efficiencies and target different brain regions, leading to diverse disease outcomes.
Prion protein structure also underlies the “species barrier,” which limits transmission between different species. The amino acid sequence of PrPC differs slightly across species, which can create a structural incompatibility between a host’s PrPC and an invading PrPSc. For a prion to jump species, the invading PrPSc must be compatible enough to convert the new host’s PrPC. The more similar the sequences and structures are, the weaker the barrier is likely to be.