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 N-15/H-1 HSQC ...
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 N-15/H-1 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 PrPSc. 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.
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