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

Abstract

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. Thismore » 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.« less

Authors:
 [1];  [2]
+ Show Author Affiliations
  1. 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)
  2. United States Department of Agriculture, Agricultural Research Service, National Animal Disease Center, Ames, IA (United States)
Publication Date:
Research Org.:
Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1494691
Grant/Contract Number:  
AC05-06OR23100
Resource Type:
Accepted Manuscript
Journal Name:
Prion
Additional Journal Information:
Journal Volume: 12; Journal Issue: 1; Journal ID: ISSN 1933-6896
Publisher:
Taylor & Francis
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Prion; chronic wasting disease; PrP; transmissible spongiform encephalopathies; cervid; CWD; amyloid; misfolding

Citation Formats

Samorodnitsky, Daniel, and Nicholson, Eric M. Differential effects of divalent cations on elk prion protein fibril formation and stability. United States: N. p., 2018. Web. doi:10.1080/19336896.2017.1423187.
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Samorodnitsky, Daniel, & Nicholson, Eric M. Differential effects of divalent cations on elk prion protein fibril formation and stability. United States. doi:10.1080/19336896.2017.1423187.
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Samorodnitsky, Daniel, and Nicholson, Eric M. Tue . "Differential effects of divalent cations on elk prion protein fibril formation and stability". United States. doi:10.1080/19336896.2017.1423187. https://www.osti.gov/servlets/purl/1494691.
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@article{osti_1494691,
title = {Differential effects of divalent cations on elk prion protein fibril formation and stability},
author = {Samorodnitsky, Daniel and Nicholson, Eric M.},
abstractNote = {Misfolding of the normally folded prion protein of mammals (PrPC) into infectious fibrils causes a variety of diseases, from scrapie in sheep to chronic wasting disease (CWD) in cervids. The misfolded form of PrPC, termed PrPSc, or in this case PrPCWD, interacts with PrPC to create more PrPCWD. 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. PrPC 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 PrPC. Other cations like manganese have also been shown to affect PrPC 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 PrPC folding pathway selection on the route to PrPSc formation.},
doi = {10.1080/19336896.2017.1423187},
journal = {Prion},
number = 1,
volume = 12,
place = {United States},
year = {2018},
month = {1}
}
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DOI:  10.1080/19336896.2017.1423187
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Figures / Tables:

Figure 1 Figure 1: Determination of Tm of Elk rPrP variants by thermal denaturation circular dichroism spectroscopy. Both rPrP L132 (A) and M132 (B) were melted in either the absence or presence of increasing molar ratios of divalent cations, copper (black circles), manganese (pink squares), calcium (blue triangles), or zinc (purple triangles).more » In the absence of divalents, both variants have similar melting temperatures – 67.16°C for L132 and 68.08°C for M132. The profile of M132 in the presence of 50x copper did not exhibit a sigmoidal shaped unfolding curve consistent with two state cooperative unfolding and could not be used to determine a Tm and is not included in this figure. In the presence of 120 mM NaCl, L132’s Tm was 64.580C and M132’s was 68.01°C.« less
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