Cryptic Peptides of the Kringle Domains Preferentially Bind to Disease-Associated Prion Protein

Abstract

Prion diseases are a group of fatal neurodegenerative disorders characterized by the accumulation of a misfolded form (PrP^Sc) of the cellular prion protein (PrP^C) in the brains of affected individuals. The conversion of PrP^C to PrP^Sc is thought to involve a change in protein conformation from a normal, primarily α-helical structure into a β-sheet conformer. Few proteins have been identified that differentially interact with the two forms of PrP. It has been reported that plasminogen binds to PrP^Sc from a variety of prion phenotypes. We have examined potential motifs within the kringle region that may be responsible for binding to PrP. We synthesized 12–15-mer peptides that contain small, repetitive stretches of amino acid residues found within the kringle domains of plasminogen. These synthetic peptides were found to capture PrP^Sc from the brain homogenates of bovine spongiform encephalopathy affected cattle, chronic wasting disease affected elk, experimental scrapie of hamsters and that of subjects affected by Creutzfeldt-Jakob disease, without binding to PrP^C in unaffected controls. Therefore, we have identified critical peptide motifs that may be important for protein-protein interactions in prion disease pathogenesis. The ability of these synthetic peptides to bind preferentially to PrP^Sc suggests a potential application in the diagnosis of prion diseases.