Polymorphisms at amino acid residues 141 and 154 influence conformational variation in ovine PrP.

Sujeong Yang,Raymond Bujdoso,Lee Hopkins,David F Burke,Alana M Thackray,Tom P Monie

doi:10.1155/2014/372491

Abstract

Polymorphisms in ovine PrP at amino acid residues 141 and 154 are associated with susceptibility to ovine prion disease: Leu141Arg154 with classical scrapie and Phe141Arg154 and Leu141His154 with atypical scrapie. Classical scrapie is naturally transmissible between sheep, whereas this may not be the case with atypical scrapie. Critical amino acid residues will determine the range or stability of structural changes within the ovine prion protein or its functional interaction with potential cofactors, during conversion of PrPC to PrPSc in these different forms of scrapie disease. Here we computationally identified that regions of ovine PrP, including those near amino acid residues 141 and 154, displayed more conservation than expected based on local structural environment. Molecular dynamics simulations showed these conserved regions of ovine PrP displayed genotypic differences in conformational repertoire and amino acid side-chain interactions. Significantly, Leu141Arg154 PrP adopted an extended beta sheet arrangement in the N-terminal palindromic region more frequently than the Phe141Arg154 and Leu141His154 variants. We supported these computational observations experimentally using circular dichroism spectroscopy and immunobiochemical studies on ovine recombinant PrP. Collectively, our observations show amino acid residues 141 and 154 influence secondary structure and conformational change in ovine PrP that may correlate with different forms of scrapie.

Highlights

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that affect humans and other vertebrate species
Characterisation of the protein folding events that occur during the conformational change in PrP during prion disease is crucial to an understanding of the formation of PrPSc and its subsequent oligomerisation
We have investigated how genotypic variation at amino acid residues 141 and 154, which are associated with susceptibility to atypical scrapie, influence conformational variation in conserved regions of the ovine prion protein

Summary

Introduction

Transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that affect humans and other vertebrate species. These conditions include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) of humans. These diseases can manifest as inherited, infectious, or sporadic conditions [1]. The globular domain demonstrates a close association between helix-1, the C-terminal region of helix-2, and the Nterminal region of helix-3. This central core is bound by an intramolecular disulphide bond between amino acid residues in helix-2 and helix-3. Characterisation of the protein folding events that occur during the conformational change in PrP during prion disease is crucial to an understanding of the formation of PrPSc and its subsequent oligomerisation

Methods

Results

Conclusion