Modeling Studies Based on NMR Models

Another factor besides PrP conformations in strain differences could be differences in PrP /PrP interaction surfaces, as with the models for species barriers discussed previously. For example, Warwicker (1997b) has interpreted his heterodimer model in light of residues important in determining strain differences. In particular, in this case, he focused on conserved and nonpolar residues and proposed that there are two distinct patches on the molecule that can interact with membrane or with a neighboring protein. This hypothesis leads to two different membrane-attached PrP orientations, or faces, that would be presented to an incoming PrP molecule. In a more recent study, Warwicker (1999) discusses how charge interactions between PrP and the membrane may affect scrapie formation. Along these lines, Morillas et al. 

Despite the heterogeneity that could result from the mechanisms described previously, the strain behavior is difficult to explain entirely by a phenomenon involving protein-protein interactions or multiple conformations of PrP . However, there is certainly evidence supporting this idea (Telling et al, 1996 Kocisko etal, 1994,1995 Bessen etal, 

PrP is a glycoprotein and the carbohydrate groups may add another level of complexity to increase the diversity of PrP =, as it is estimated that 401 different PrP glycoforms are possible (Endo et al, 

PrP molecules from different prion strains differ in size and state of glycosylation (Stahl et al, 1993), and there can be differences in glycosylation of PrP versus PrP (Rudd et al, 1999). DeArmond et al. 

The NMR spectroscopists and other modelers have explored the possible structural basis for the familial prion diseases. The premise is that inherited prion diseases are due to destabilization of PrP on mutation, which facilitates PrP = production. The known human disease causing mutations (Fig. 1) have been mapped onto the extended human NMR 

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