Dynamics of a truncated prion protein, PrP(113–231), from 15 N NMR relaxation: Order parameters calculated and slow conformational fluctuations localized to a distinct region

Prion diseases are associated with the misfolding of the prion protein (PrP C ) from a largely α‐helical isoform to a β‐sheet rich oligomer (PrP Sc ). Flexibility of the polypeptide could contribute to the ability of PrP C to undergo the conformational rearrangement during PrP C –PrP Sc interactions, which then leads to the misfolded isoform. We have therefore examined the molecular motions of mouse PrP C , residues 113–231, in solution, using 15 N NMR relaxation measurements. A truncated fragment has been used to eliminate the effect of the 90‐residue unstructured tail of PrP C so the dynamics of the structured domain can be studied in isolation. 15 N longitudinal ( T 1 ) and transverse relaxation ( T 2 ) times as well as the proton‐nitrogen nuclear Overhauser effects have been used to calculate the spectral density at three frequencies, 0, ω N, and 0.87ω H . Spectral densities at each residue indicate various time‐scale motions of the main‐chain. Even within the structured domain of PrP C , a diverse range of motions are observed. We find that removal of the tail increases T 2 relaxation times significantly indicating that the tail is responsible for shortening of T 2 times in full‐length PrP C . The truncated fragment of PrP has facilitated the determination of meaningful order parameters ( S 2 ) from the relaxation data and shows for the first time that all three helices in PrP C have similar rigidity. Slow conformational fluctuations of mouse PrP C are localized to a distinct region that involves residues 171 and 172. Interestingly, residues 170–175 have been identified as a segment within PrP that will form a steric zipper, believed to be the fundamental amyloid unit. The flexibility within these residues could facilitate the PrP C –PrP Sc recognition process during fibril elongation.