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Indexed/Abstracted in: BIOSIS Previews, Current Contents/Clinical Medicine, EMBASE, PubMed/MEDLINE, Science Citation Index Expanded (SciSearch), Scopus
Impact Factor 1,6
Online ISSN 1827-1898
Wong B.-S., Brown D. R. *, Sy M.-S.
From the Institute of Pathology Case Western Reserve University School of Medicine Cleveland, Ohio, USA
*Department of Biochemistry, Cambridge University Cambridge, UK
Prion diseases are not only genetic or sporadic neurodegenerative disorders, but more important, they are transmissible diseases. The etiological agent in these unprecedented diseases is believed to be prion protein (PrP), which undergoes post-translational conversion from the predominant α-helical conformation known as PrPC, to a β-sheet rich abnormal isoform called scrapie PrP (PrPSc). Accumulating evidence has shown PrPC to be a copper-binding antioxidant in vivo. The prevailing view that PrP binds copper weakly is based on in vitro observations using peptides or short fragment of recombinant PrP. However, recent in vitro evidence indicates human PrP has significantly higher affinity for copper, similar to other copper-binding proteins and copper uptake experiments show that PrP expressed by cells has a Km in the nanomolar range. Besides binding copper within the octarepeats region along the N-terminus, PrP can also binds copper at a second site further upstream. More importantly, PrP also binds other metals such as zinc and manganese at these two sites albeit at a lower affinity. This is important because there is evidence that native PrP in prion diseases binds not only copper, but also zinc. This abnormal metal binding probably resulted in the loss of its anti-oxidation function, and together with impairment in the cellular antioxidant mechanisms, contributed to the increased oxidative stress, and possibly trigger neurodegeneration.