Abstract
Human (huPrP) and Syrian hamster (ShaPrP) prion proteins have barriers for mutual infectivity, although they fold into almost an identical structure. The pressure responses of huPrP and ShaPrP characterized by high pressure NMR spectroscopy show differences in their excited states, as monitored by pressure-induced chemical shifts and intensity changes of individual residues in the (15)N/(1)H HSQC spectra. Both proteins fluctuate rapidly between two well folded (native) conformations N(1) and N(2) and less frequently between N and the excited states I(1) and I(2) with local disorder that may present structural intermediates on the way to PrP(Sc). These four structural states can be observed in the hamster and human PrP. At ambient pressure, less than 5 molecules of 10,000 are in the intermediate state I(2). From the structural point of view, the different states are mutually different, particularly in positions strategically important for generating species barriers for infection. The results point to the notion that excited state conformers are important for infection and that their structural differences may crucially determine species barriers for infection.
Highlights
Transmissible spongiform encephalopathies are associated with the formation of an oligomeric conformational scrapie isomer, PrPSc, of the host-encoded monomeric prion protein PrPC [1]
A puzzle of this hypothesis is the existence of a wide variety of distinct so-called prion strains with differing infectivity and related to them a
The differences in PrPSc amino acid sequence related to heterology of the PrP genotype may account for the formation of distinct prion strains and for the species barrier [6]
Summary
Transmissible spongiform encephalopathies are associated with the formation of an oligomeric conformational scrapie isomer, PrPSc, of the host-encoded monomeric prion protein PrPC [1]. The differences in PrPSc amino acid sequence related to heterology of the PrP genotype may account for the formation of distinct prion strains and for the species barrier [6]. For this reason, hamster prions are usually not infectious to wild-type mice, and there is a moderate species barrier for transmission of mouse prions to hamster. The amino acid sequences of all mammalian prion proteins are rather similar (e.g. see Fig. 1), and global folds are well conserved This indicates that the basic folded structures themselves cannot tell the molecular mechanism for the species barrier for infection. We have analyzed the two high pressure NMR data sets from the two proteins in an identical manner to find the similarity and differences in their excited state conformers
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