Prion diseases are neurodegenerative disorders caused by the misfolding of the cellular prion protein (PrPC). Gerstmann-Sträussler-Scheinker syndrome is an inherited prion disease with one early-onset allele (HRdup) containing an eight-amino-acid insertion; this LGGLGGYV insert is positioned after valine 129 (human PrPC sequence) in a hydrophobic tract in the natively disordered region. Here we have characterized the structure and explored the molecular motions and dynamics of HRdup PrP and a control allele. High-resolution NMR data suggest that the core of HRdup has a canonical PrPC structure, yet a nascent β-structure is observed in the flexible elongated hydrophobic region of HRdup. In addition, using mouse PrPC sequence, we observed that a methionine/valine polymorphism at codon 128 (equivalent of methionine/valine 129 in human sequence) and oligomerization caused by high protein concentration affects conformational exchange dynamics at residue G130. We hypothesize that with the β-structure at the N-terminus, the hydrophobic region of HRdup can adopt a fully extended configuration and fold back to form an extended β-sheet with the existing β-sheet. We propose that these structures are early chemical events in disease pathogenesis.
Keywords: GSS disease; NMR structure; motion dynamics; oligomerization; prion protein.
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