TY - JOUR
T1 - Cellular prion protein gene polymorphisms linked to differential scrapie susceptibility correlate with distinct residue connectivity between secondary structure elements
AU - Soto, Patricia
AU - Claflin, India A.
AU - Bursott, Alyssa L.
AU - Schwab-McCoy, Aimee D.
AU - Bartz, Jason C.
N1 - Funding Information:
The authors acknowledge the Creighton University Center for Undergraduate Research and Scholarship (CURAS) for partial funding. This work was made possible partly by grants from the National Institute for General Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of Health (NIH), and its contents are the sole responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. The authors acknowledge Noah Yoshida who performed preliminary analysis of the structures.
PY - 2021
Y1 - 2021
N2 - The conformational conversion of the cellular prion protein (PrPC) to the misfolded and aggregated isoform, termed scrapie prion protein (PrPSc), is key to the development of a group of neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). Although the conversion mechanism is not fully understood, the role of gene polymorphisms in varying susceptibilities to prion diseases is well established. In ovine, specific gene polymorphisms in PrPC alter prion disease susceptibility: the Valine136–Glutamine171 variant (Susceptible structure) displays high susceptibility to classical scrapie while the Alanine136–Arginine171 variant (Resistant structure) displays reduced susceptibility. The opposite trend has been reported in atypical scrapie. Despite the differentiation between classical and atypical scrapie, a complete understanding of the effect of polymorphisms on the structural dynamics of PrPC is lacking. From our structural bioinformatics study, we propose that polymorphisms locally modulate the network of residue interactions in the globular C-terminus of the ovine recombinant prion protein while maintaining the overall fold. Although the two variants we examined exhibit a densely connected group of residues that includes both β-sheets, the β2–α2 loop and the N-terminus of α-helix 2, only in the Resistant structure do most residues of α-helix 2 belong to this group. We identify the structural role of Valine136Alanine and Glutamine171Arginine: modulation of residue interaction networks that affect the connectivity between α-helix 2 and α-helix 3. We propose blocking interactions of residue 171 as a potential target for the design of therapeutics to prevent efficient PrPC misfolding. We discuss our results in the context of initial PrPC conversion and extrapolate to recently proposed PrPSc structures. Communicated by Ramaswamy H. Sarma.
AB - The conformational conversion of the cellular prion protein (PrPC) to the misfolded and aggregated isoform, termed scrapie prion protein (PrPSc), is key to the development of a group of neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). Although the conversion mechanism is not fully understood, the role of gene polymorphisms in varying susceptibilities to prion diseases is well established. In ovine, specific gene polymorphisms in PrPC alter prion disease susceptibility: the Valine136–Glutamine171 variant (Susceptible structure) displays high susceptibility to classical scrapie while the Alanine136–Arginine171 variant (Resistant structure) displays reduced susceptibility. The opposite trend has been reported in atypical scrapie. Despite the differentiation between classical and atypical scrapie, a complete understanding of the effect of polymorphisms on the structural dynamics of PrPC is lacking. From our structural bioinformatics study, we propose that polymorphisms locally modulate the network of residue interactions in the globular C-terminus of the ovine recombinant prion protein while maintaining the overall fold. Although the two variants we examined exhibit a densely connected group of residues that includes both β-sheets, the β2–α2 loop and the N-terminus of α-helix 2, only in the Resistant structure do most residues of α-helix 2 belong to this group. We identify the structural role of Valine136Alanine and Glutamine171Arginine: modulation of residue interaction networks that affect the connectivity between α-helix 2 and α-helix 3. We propose blocking interactions of residue 171 as a potential target for the design of therapeutics to prevent efficient PrPC misfolding. We discuss our results in the context of initial PrPC conversion and extrapolate to recently proposed PrPSc structures. Communicated by Ramaswamy H. Sarma.
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U2 - 10.1080/07391102.2019.1708794
DO - 10.1080/07391102.2019.1708794
M3 - Article
C2 - 31900058
AN - SCOPUS:85078618519
VL - 39
SP - 129
EP - 139
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
SN - 0739-1102
IS - 1
ER -