Abstract
Prion Proteins (PrP) are among a small number of proteins for which large numbers of NMR ensembles have been resolved for sequence mutants and diverse species. Here, we perform a comprehensive principle components analysis (PCA) on the tertiary structures of PrP globular proteins to discern PrP subdomains that exhibit conformational change in response to point mutations and clade-specific evolutionary sequence mutation trends. This is to our knowledge the first such large-scale analysis of multiple NMR ensembles of protein structures, and the first study of its kind for PrPs. We conducted PCA on human (n = 11), mouse (n = 14), and wildtype (n = 21) sets of PrP globular structures, from which we identified five conformationally variable subdomains within PrP. PCA shows that different non-local patterns and rankings of variable subdomains arise for different pathogenic mutants. These subdomains may thus be key areas for initiating PrP conversion during disease. Furthermore, we have observed the conformational clustering of divergent TSE-non-susceptible species pairs; these non-phylogenetic clusterings indicate structural solutions towards TSE resistance that do not necessarily coincide with evolutionary divergence. We discuss the novelty of our approach and the importance of PrP subdomains in structural conversion during disease.
Highlights
The extraordinary conformational change witnessed between the normal, non-pathological prion protein, PrPC, and its virulent pathological form, PrPSC, in which the latter acquires substantial bsheet content, is a significant contributor to the role this protein plays as an agent of many incurable Transmission Spongiform Encephalopathies (TSEs)
Prion Proteins (PrP) cause a variety of incurable TSE diseases, and are among a small number of proteins for which large numbers of NMR ensembles have been resolved for sequence mutants and diverse species
We perform a comprehensive Principal Component Analysis (PCA) study to assess conformational variation and discern the landscape of the PrP structural response to sequence mutation. This is to our knowledge the first large-scale analysis of multiple NMR ensembles for a specific protein, and the first study to perform a multivariate PCA on the native globular structures of PrP
Summary
The extraordinary conformational change witnessed between the normal, non-pathological prion protein, PrPC, and its virulent pathological form, PrPSC, in which the latter acquires substantial bsheet content, is a significant contributor to the role this protein plays as an agent of many incurable Transmission Spongiform Encephalopathies (TSEs). Such diseases, including human Creutzfeldt-Jakob Disease (CJD) and Bovine Spongiform Encephalopathy (BSE), are caused by the misfolding and subsequent aggregation of PrPSC to produce amyloid fibrils, highly ordered and distinct bsheet-rich molecular aggregates [1,2]. The prion protein is one of few proteins with a large number of pathogenic mutants, and the increasing availability of these structures in the protein databank (PDB) provides ample material for a multivariate analysis of structural plasticity of PrP domains
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