On our initial discovery that
prion protein (
PrP)-
derived peptides were capable of capturing the
pathogenic prion protein (
PrP(Sc)), we have been interested in how these
peptides interact with
PrP(Sc). After screening
peptides from the entire human
PrP sequence, we found two
peptides (
PrP(19-30) and
PrP(100-111)) capable of binding full-length
PrP(Sc) in plasma, a medium containing a complex mixture of other proteins including a vast excess of the normal
prion protein (
PrP(C)). The limit of detection for captured
PrP(Sc) was calculated to be 8 amol from a approximately 10(5)-fold dilution of 10% (wt/vol) human
variant Creutzfeldt-Jakob disease brain homogenate, with >3,800-fold binding specificity to
PrP(Sc) over
PrP(C). Through extensive analyses, we show that positively charged
amino acids play an important, but not exclusive, role in the interaction between the
peptides and
PrP(Sc). Neither hydrophobic nor polar interactions appear to
correlate with binding activity. The peptide-PrP(Sc) interaction was not sequence-specific, but
amino acid composition affected binding. Binding occurs through a conformational domain that is only present in
PrP(Sc), is species-independent, and is not affected by
proteinase K digestion. These and other findings suggest a mechanism by which
cationic domains of
PrP(C) may play a role in the recruitment of
PrP(C) to
PrP(Sc).
