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Nascent β Structure in the Elongated Hydrophobic Region of a Gerstmann–Sträussler–Scheinker PrP Allele

Fu, Ze-Lin, Holmes, Peter C., Westaway, David, Sykes, Brian D.
Journal of molecular biology 2019 v.431 no.14 pp. 2599-2611
alleles, humans, hydrophobicity, inheritance (genetics), methionine, mice, neurodegenerative diseases, nuclear magnetic resonance spectroscopy, oligomerization, pathogenesis, prion diseases, prions, valine
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.