Putative aggregation initiation sites in prion protein.
Misfolded prion protein, PrPSc, is believed to be the pathogenic agens in transmissible spongiform encephalopathies. Little is known about the autocatalytic misfolding process. Looking at the intrinsic properties of short sequence stretches, such as conformational flexibility and the tendency to populate extended conformers, we have examined the aggregation behaviour of various peptides within the region 106-157 of the sequence of human prion protein. We observed fast aggregation for the peptide containing residues I138-I-H-F141. This sequence, which is presented at the surface of cellular prion protein, PrPC, in an almost beta-sheet-like conformation, is therefore an ideal anchor-point for initial intermolecular contacts leading to oligomerization. We further report that the aggregation propensity of the neurotoxic peptide 106-126 appears to be centred in its termini and not in the central, alanine-rich sequence (A113-G-AAAA-G-A120).
Lehrstuhl Biopolymere, University Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany.
Jan
J
Ziegler
Christine
C
Viehrig
Stefan
S
Geimer
Paul
P
Rösch
Stephan
S
Schwarzinger
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D020836:Protein Structure, Quaternary
D000682:Amyloid; D010446:Peptide Fragments; D018621:PrPC Proteins; D000409:Alanine