A physicochemical approach to the structure of the PrPC prion protein : Conformational plasticity of peptides of the 121-170 (H1-S2) region of the ovine prion protein

Abstract

The conversion of the prion protein from the normalnon-pathogenic cellular form (PrPC), to the pathogenicmisfolded isoform (PrPSc) involves an increase of theamount of beta sheet in the protein structure, whichfavours aggregation, formation of fibrils and resistanceto proteinase K. The three-dimensional structure ofPrPc, which has been determined for four species, isextremely conserved. It contains a flexible segment atthe N-terminus and a globular part composed of twobeta-strands (S1, S2) and three alpha-helices (H1 to H3) associated by loops (L1 to L5). The protein fragmentcorresponding to helix H1 is an autonomousregion that can adopt a helical structure by itself. Bycontrast, the peptide that contains region H1-L3-S2(PrPH1-L3-S2) adopts different conformations, as alsoshown for the protein. These results allow proposinghelix H1 as one of the structural motifs of the prionprotein able to initiate the transconformation, i.e. theconversion of the benign prion protein into its pathogenicisoform. The key role played by helix H1 in thetransconformation was analysed in a physicochemicalstudy using a series of peptides of different sequencesand lengths (9 to 33 residues, sheep sequence) designedin the [133-165] region that contains the structuralmotifs L2-H1-L3-S2. The main results, which aredescribed here, show the great stability of helix H1,particularly in the presence of either loop L2 or loopsL2 and L3. The absence of loop L2 associated to thepresence of beta-strand S2 decreases the stability ofhelix H1. It is possible that loop L2 could play a specialrole, as suggested by the fact that this loop can interactwith PrPC. Such an interaction could contribute tothe mechanisms that are involved in the interactionbenign prion protein / pathogenic prion protein, whichis implicated in the propagation of the disease. Theseresults, which should be confirmed and developped,lead to propose loop L2 and strand S2 as two regionsthat could assume a "regulation" of the stability ofhelix H1, which appears as a key region in the pathogenicconversion process.