PrPSc structural models

Low-resolution optical spectroscopic measurements established that the PrPc—>PrPSc conversion is accompanied by a major decrease in a-helical content and an increase in (3-sheet structure [101-104]. However, the secondary structure of PrPSc remains controversial, with the estimated content of a-helical structure ranging from 0%, as assessed by circular dichroism spectroscopy [104], to 0-21%, as inferred from Fourier-transform infrared measurements [101-103, 105]. These low resolution spectroscopic measurements are subject to considerable uncertainty thus, caution should be exercised when using global secondary structure estimates for constructing specific high-resolution structural models of PrPSc. 

All three of these predictions from this minimal model are manifest in the etiology of prion disease an inversely proportional relationship between PrPc expression and prion incubation period in transgenic mice predisposition by relatively subtle mutations in the protein sequence and a requirement for molecular homogeneity between PrPSc and PrPc for efficient prion propagation [4, 5, 20]. It is clear that a full understanding of prion propagation will require knowledge both of the structure of PrPc and PrPSc and of the mechanism of conversion between them. 

Fig. 4. The molecular structure, determined by solution NMR (James et al., 1997), of Syrian hamster 90-231 (SHa90-231) prion with ball-and-stick representation of the HI domain (SHal09-122 MKHMAGAAAAGAW). Note that two short /(-chains (SI, S2) nearly stack in the hydrogen-bonding direction. If the palindromic polyalanine region was also in a /(-conformation, there would be a three-stranded /(-sheet. The structural difference between PrPc and PrPSc is in the 90-145 domain. [Model drawn using MOLSCRIPT (Kraulis, 1991)].

Fig. 5 Models of prion replication, (a) The template assistance model predicts that a PrPSo monomer is more stable than PrPc, but is kinetically inaccessible. In the rare event that a PrPSo monomer is created spontaneously (or provided exogenously), it can template the misfolding of another PrPc molecule by direct interaction. The dashed line shows that the newly created PrPSc monomer can act as another seed to formation of PrPSc. (b) The nucleation polymerization model predicts that barrier to prion protein conversion is the formation of a nucleus in which the protein adopts a PrPSo-like structure. The formation of such a low order aggregate is not favored however, once it has formed, polymerization from a pool of PrPc molecules can take place efficiently. Fragmentation of the polymer increases the number of ends for the recruitment of PrPc monomers...

One of the most difficult challenges in the TSE field is the determination of the atomic structure of PrPSc. While a number of approaches have recently emerged to probe the structure of ordered protein aggregates, most of them require the introduction of specific spectroscopic probes therefore, they are not applicable to proteins derived from mammalian tissue. In the absence of direct experimental data, the structures proposed for PrPSc are largely based on modeling efforts. 

On the experimental front, the structure of PrPSc derived from brain tissue of scrapie-infected transgenic mice expressing GPI-free prion protein was recently examined by the hydrogen/deuterium exchange method [105], In contrast to the models described above, these data indicate that the PrPc >PrPSc conversion involves major refolding of the entire region C-terminal to residue 80-90, and that this region in PrPSc consists of a network of (3-strands and relatively short turns, with no native a-helices present. 

The next year Huang et at. (1995) extended their prediction studies to PrP. In this case they made use of the conformational ambivalence of HI and H2 and predicted that they would be the segments of the structure to undergo a conformational transition in the formation of PrpSc Various packing arrangements were considered, and the preferred model is displayed in Fig. 2 alongside PrP. This model retains helices H3 and H4, while HI and H2 are extended and form a (3 sheet on the helical scaffold. 

Despite the NMR structures now available, modeling and simulations studies are still necessary for the following reasons (1) both PrP and PrpSc conformationally heterogeneous, (2) the PrR" structures were... 

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