ABSTRACT Prion proteins cause neurodegenerative illnesses in humans and animals. The diseases are associated with a topological change from a predominantly alpha (PrP^sup c^) to gamma-sheet (PrP^sup sc^) structure. Many studies have focused on the minimum sequence requirements and key events for developing or transmitting disease. Here, we report on the application of molecular modeling studies to predict the lowest-energy conformations for five fragments in solution at pH 7. We show that PrP(143-- 158) adopts a helix, the model PrP(106-126), PrP(142-167), and PrP(143-178) peptides have a clear preference for a variety of beta-sheet structures, whereas PrP(127-164) has two iso-energetic conformations with all beta or alphabeta native-like structures. Such a finding for PrP(127-164), which explains a large body of experimental data, including the location of all mutations causing prion diseases, may have important implications for triggering or propagating the topological change.
In summary, we have shown that both PrP(106-126) and PrP(127-164) are prone to form scrapie-like beta structures. In contrast to PrP(106-126) and previous model peptides studied (Derreumaux, 1999, 2000), which are predicted to be in equilibrium between their native topologies and random coil conformations, PrP(127-164) is found to code for two distinct topologies with comparable energies in isolation. Because strand S2 interacts with helices H2 and H3, the extrapolation of this energetic result to the behavior of the full PrP protein in vivo remains to be validated. Nevertheless, this conformational distribution clarifies a large body of experimental aspects and provides a simple explanation for propagating and/or triggering the PrP topological change.
I am indebted to Serguei Kozin for providing me with the NMR structure of mPrP(142-167) and for numerous discussions. I also thank Pascale Debey, Vincent Monchois, Yves-Henri Sanejouand, and the anonymous referees for helpful comments.
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Information Genetique et Structurale, CNRS-UMR 1889, 13402 Marseille, France
Received for publication 31 January 2001 and in final form 14 May 2001.
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