Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein

Agarwal, Sonya, Döring, Kristina, Gierusz, Leszek A. , Iyer, Pooja, Lane, Fiona M., Graham, James F., Goldmann, Wilfred, Pinheiro, Teresa J. T. and Gill, Andrew C. (2015) Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein. Scientific Reports, 5 (1). ISSN 2045-2322

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The β2–α2 loop of PrPC is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrPC appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the β2–α2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that ‘rigidity’ in the β2–α2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region.

Keywords:prion, protein misfolding, transmissible spongiform encephalopathies
Subjects:D Veterinary Sciences, Agriculture and related subjects > D320 Animal Health
C Biological Sciences > C770 Biophysical Science
C Biological Sciences > C760 Biomolecular Science
B Subjects allied to Medicine > B140 Neuroscience
Divisions:College of Science
ID Code:29465
Deposited On:13 Nov 2017 17:05

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