Differential effects of divalent cations on elk prion protein fibril formation and stability

Samorodnitsky, Daniel; Nicholson, Eric M.

doi:10.1080/19336896.2017.1423187

Title: Differential effects of divalent cations on elk prion protein fibril formation and stability

Journal Article · Tue Jan 09 00:00:00 EST 2018 · Prion

DOI:https://doi.org/10.1080/19336896.2017.1423187· OSTI ID:1494691

Samorodnitsky, Daniel ^[1]; Nicholson, Eric M. ^[2]

Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States); United States Department of Agriculture, Agricultural Research Service, National Animal Disease Center, Ames, IA (United States)
United States Department of Agriculture, Agricultural Research Service, National Animal Disease Center, Ames, IA (United States)

Misfolding of the normally folded prion protein of mammals (PrP^C) into infectious fibrils causes a variety of diseases, from scrapie in sheep to chronic wasting disease (CWD) in cervids. The misfolded form of PrP^C, termed PrP^Sc, or in this case PrP^CWD, interacts with PrP^C to create more PrP^CWD. This process is not clearly defined but is affected by the presence and interactions of biotic and abiotic cofactors. These include nucleic acids, lipids, glycosylation, pH, and ionic character. PrP^C has been shown to act as a copper-binding protein in vivo, though it also binds to other divalents as well. The significance of this action has not been conclusively elucidated. Previous reports have shown that metal binding sites occur throughout the N-terminal region of PrP^C. Other cations like manganese have also been shown to affect PrP^C abundance in a transcript-independent fashion. Here, we examined the ability of different divalent cations to influence the stability and in vitro conversion of two variants of PrP from elk (L/M132, 26–234). We find that copper and zinc destabilize PrP. We also find that PrP M132 exhibits a greater degree of divalent cation induced destabilization than L132. This supports findings that leucine at position 132 confers resistance to CWD, while M132 is susceptible. However, in vitro conversion of PrP is equally suppressed by either copper or zinc, in both L132 and M132 backgrounds. This report demonstrates the complex importance of ionic character on the PrP^C folding pathway selection on the route to PrP^Sc formation.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-06OR23100

OSTI ID:: 1494691

Journal Information:: Prion, Vol. 12, Issue 1; ISSN 1933-6896

Publisher:: Taylor & FrancisCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 6 works

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59 BASIC BIOLOGICAL SCIENCES
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