Abstract
The conversion of prion helix 1 from an alpha-helical into an extended conformation is generally assumed to be an essential step in the conversion of the cellular isoform PrPC of the prion protein to the pathogenic isoform PrPSc. Peptides encompassing helix 1 and flanking sequences were analyzed by nuclear magnetic resonance and circular dichroism. Our results indicate a remarkably high instrinsic helix propensity of the helix 1 region. In particular, these peptides retain significant helicity under a wide range of conditions, such as high salt, pH variation, and presence of organic co-solvents. As evidenced by a data base search, the pattern of charged residues present in helix 1 generally favors helical structures over alternative conformations. Because of its high stability against environmental changes, helix 1 is unlikely to be involved in the initial steps of the pathogenic conformational change. Our results implicate that interconversion of helix 1 is rather representing a barrier than a nucleus for the PrPC-->PrPSc conversion.
Highlights
Helix 1 has to undergo complete structural rearrangement from helical conformation to a -sheet conformation according to recent structural model derived from cryoelectron crystallography of two-dimensional crystals of prion protein (15)
Because helix 1 is embedded in parts in the structure that already adopt in large part a -sheet or extended conformation in PrPC, it is likely that this helix is one of the final parts of prion protein that changes its structure in a local unfolding event
As the model of PrPSc devised by Wille et al (15) proposes the incorporation of helix 1 into the parallel -helix forming the main part of prion amyloid, the high stability of helix 1 could be part of a barrier needed to prevent the spontaneous conversion of PrPC to PrPSc (55)
Summary
High residual helix contents can be observed in the polar sequence stretch M57-SEED-L62 of unfolded apo-plastocyanin (51). Implications for the Conversion Reaction—Our observations lead to the question of how helix 1, being remarkably stable against environmental and mutational changes, is involved in the conformational conversion of PrPC to PrPSc. In particular, helix 1 has to undergo complete structural rearrangement from helical conformation to a -sheet conformation according to recent structural model derived from cryoelectron crystallography of two-dimensional crystals of prion protein (15).
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