Effects of Cu2+ on conformational change and aggregation of hPrP180-192 with a V180I mutation of the prion protein.


Laboratory of Bio-analytical Chemistry, Faculty of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan; Department of Pharmacy, Japanese Red Cross Kyoto Daiichi Hospital, 15-749 Honmachi, Higashiyama-ku, Kyoto, Kyoto, 605-0981, Japan. Electronic address: [Email]


Prion diseases are neurodegenerative disorders caused by misfolding of the prion protein (PrP) from a normal cellular protein (PrPC) to a protease-resistant isoform (PrPSc). However, the aggregation mechanism is not entirely understood because of the physical properties of PrP, such as its solubility or aggregation in vitro and conformational or mutation diversity. Recently, we reported the physical and physiological properties of a synthetic fragment peptide. In the present study, we assessed the importance of a point mutation at the C-terminal region of PrP in structural conversion and aggregation and evaluated the physical and physiological properties of the point-mutated human-PrP180-192 V180I (hPrP180-192 V180I) using circular dichroism spectra, high-performance liquid chromatography, Affinix QNμ, and thioflavin-T staining, including the effects of Cu2+. The secondary structure of hPrP180-192 V180I changed from a random coil to a β-sheet in Cu2+ free buffer. In addition, we observed molecular interactions in hPrP180-192 V180I and aggregation with itself, which were inhibited by Cu2+. We conclude that the point mutation in the C-terminal region of PrP, including hPrP180-192 V180I, and Cu2+ may play an important role in the conversion of PrPC to PrPSc.


Aggregation,Circular dichroism spectra,Cu(2+),HPLC analysis,Intermolecular interaction,Point-mutated hPrP180-192,Prion protein,Structural conversion,Thioflavin-T,

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