Inverse Correlation of Thermal Lability and Conversion Efficiency for Five Prion Protein Polymorphic Variants

Kirby, Louise and Agarwal, Sonya and Graham, James F. and Goldmann, Wilfred and Gill, Andrew (2010) Inverse Correlation of Thermal Lability and Conversion Efficiency for Five Prion Protein Polymorphic Variants. Biochemistry, 49 (7). pp. 1448-1459. ISSN 0006-2960

Full content URL: https://pubs.acs.org/doi/abs/10.1021/bi901855z

Documents
Inverse Correlation of Thermal Lability and Conversion Efficiency for Five Prion Protein Polymorphic Variants

Request a copy
[img] PDF
Kirby1448.pdf - Whole Document
Restricted to Repository staff only

2MB
Item Type:Article
Item Status:Live Archive

Abstract

Transmissible spongiform encephalopathies (TSEs) are associated with the accumulation of
deposits of an abnormal form, PrPSc, of the host-encoded prion protein, PrPC. Amino acid substitutions in
PrPC have long been known to affect TSE disease outcome. In extreme cases in humans, various mutations
appear to cause disease. In animals, polymorphisms are associated with variations in disease susceptibility
and, in sheep, several polymorphisms have been identified that are known to affect susceptibility of carriers to
disease. The mechanisms of polymorphism-mediated modulation of disease susceptibility remain elusive, and
we have been studying the effect of various amino acid substitutions at PrP codon 164 (mouse numbering), in
the β2-R2 loop region of the prion protein, to attempt to decipher how polymorphisms may affect disease
susceptibility. Combined in vitro approaches suggest that there exists a correlation between the ability of
protein variants to convert to abnormal isoforms in seeded conversion assays versus the thermal stability of
the protein variants, as judged by both thermal denaturation and an unseeded in vitro oligomerization assay.
We have performed molecular dynamics simulations to give an indication of backbone conformational
changes as a result of amino acid changes and found that alteration of a single residue in PrP can result in local
changes in structure that may affect global conformation and stability. Our results are consistent with
modulation of disease susceptibility through differential protein stability leading to enhanced generic
misfolding of TSE resistance-associated protein variants.

Additional Information:The final published version of this article is available online at https://pubs.acs.org/doi/abs/10.1021/bi901855z
Keywords:Prion, Protein misfolding, transmissible spongiform encephalopathies, Protein Structure, Secondary, Molecular dynamics
Subjects:C Biological Sciences > C760 Biomolecular Science
B Subjects allied to Medicine > B140 Neuroscience
C Biological Sciences > C770 Biophysical Science
D Veterinary Sciences, Agriculture and related subjects > D320 Animal Health
Divisions:College of Science
ID Code:29479
Deposited On:30 Aug 2018 14:33

Repository Staff Only: item control page