Cellular prion protein conformation and function

Abstract

In the otherwise highly conserved NMR structures of cellular prion proteins (PrP C) from different mammals, species variations in a surface epitope that includes a loop linking a β-strand, β2, with a helix, α2, are associated with NMR manifestations of a dynamic equilibrium between locally different conformations. Here, it is shown that this local dynamic conformational polymorphism in mouse PrP C is eliminated through exchange of Tyr169 by Ala or Gly, but is preserved after exchange of Tyr 169 with Phe. NMR structure determinations of designed variants of mouse PrP(121-231) at 20 °C and of wild-type mPrP(121-231) at 37 °C together with analysis of exchange effects on NMR signals then resulted in the identification of the two limiting structures involved in this local conformational exchange in wild-type mouse PrP C, and showed that the two exchanging structures present characteristically different solvent-exposed epitopes near the β2-α2 loop. The structural data presented in this paper provided a platform for currently ongoing, rationally designed experiments with transgenic laboratory animals for renewed attempts to unravel the so far elusive physiological function of the cellular prion protein.