UV-light-induced conversion and aggregation of prion proteins.
Increasing evidence suggests a central role for oxidative stress in the pathology of prion diseases, a group of fatal neurodegenerative disorders associated with structural conversion of the prion protein (PrP). Because UV-light-induced protein damage is mediated by direct photo-oxidation and radical reactions, we investigated the structural consequences of UVB radiation on recombinant murine and human prion proteins at pH 7.4 and pH 5.0. As revealed by circular dichroism and dynamic light scattering measurements, the observed PrP aggregation follows two independent pathways: (i) complete unfolding of the protein structure associated with rapid precipitation or (ii) specific structural conversion into distinct soluble beta-oligomers. The choice of pathway was directly attributed to the chromophoric properties of the PrP species and the susceptibility to oxidation. Regarding size, the oligomers characterized in this study share a high degree of identity with oligomeric species formed after structural destabilization induced by other triggers, which significantly strengthens the theory that partly unfolded intermediates represent initial precursor molecules directing the pathway of PrP aggregation. Moreover, we identified the first suitable photo-trigger capable of inducing refolding of PrP, which has an important biotechnological impact in terms of analyzing the conversion process on small time scales.
Redecke
Lars
L
Institute of Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, Germany.
Binder
Stephan
S
Elmallah
Mohammed I Y
MI
Broadbent
Rebecca
R
Tilkorn
Claudia
C
Schulz
Benjamin
B
May
Patrick
P
Goos
Arne
A
Eich
Andreas
A
Rübhausen
Michael
M
Betzel
Christian
C
D000818:Animals; D002942:Circular Dichroism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D010084:Oxidation-Reduction; D018621:PrPC Proteins / Q000737:chemistry* / Q000528:radiation effects; D018620:PrPSc Proteins / Q000737:chemistry / Q000528:radiation effects; D017096:Prion Diseases / Q000209:etiology / Q000503:physiopathology*; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry* / Q000528:radiation effects; D012995:Solubility; D014466:Ultraviolet Rays
D018621:PrPC Proteins; D018620:PrPSc Proteins; D011994:Recombinant Proteins