The origins of toxic prion peptide, PrPSc
PrPSc originates from a prion precursor protein, PrP. PrP undergoes removal of 22 aa in the endoplasmic reticulum and additional removal of 23 aa after the addition of the cell surface anchor, glycosylphosphatidylinositol, to form PrPC. PrPC is non-toxic, however, for reasons that are still unclear, some PrPC proteins misfold and are converted to the disease version of the protein, PrPSc.
PrPC and PrPSc have the same amino acid sequence, however, due to differences in protein folding, PrPC is composed of alpha-helices, whereas beta-sheets are prominent in pathogenic PrPSc. These differences in secondary structure affect tertiary and quaternary structure with important consequences: PrPC is easily solubilized and protease-labile, while PrPSc is largely insoluble and protease-resistant, rendering it resistant to conventional means of degradation. More importantly, PrPSc catalyzes the conformational change of PrPC to PrPSc. Thus, every converted PrPC protein becomes a catalyst for the production of more PrPSc, whose proliferation results in the neurodegenerative ailments listed above. Hence, PrPSc-PrPC interactions are considered therapeutic targets.
Complicating studies of prion diseases is the fact that the physiological role of PrPC has not yet been fully determined. It is hypothesized that PrPC is involved in neural plasticity, in which PrPC interacts with numerous other proteins. One of these proteins is laminin, for which PrPC is a receptor. The gamma peptide chain of laminin (laminin γ1) contains the binding site for PrPC, therefore laminin γ1 is useful in assays designed to determine the effects of PrPC- laminin γ1 binding and the role of PrPC.
Peptides in prion-related disease therapeutic research
Prion peptide therapeutics are typically designed to prevent PrPC and PrPSc interactions. Drug designs include inhibitors of PrPC- PrPSc binding.
