The amino-terminal PrP domain is crucial to modulate prion misfolding and aggregation

The main hypothesis for prion diseases is that the cellular protein ( PrPC) can be altered into a misfolded, beta- sheet-rich isoform ( PrPSc), which undergoes aggregation and triggers the onset of transmissible spongiform encephalopathies. Here, we investigate the effects of amino- terminal deletion mutations, rPrP(Delta 51 - 90) and rPrP(Delta 32) (- 121), on the stability and the packing properties of recombinant murine PrP. The region lacking in rPrP(Delta 51 - 90) is involved physiologically in copper binding and the other construct lacks more amino- terminal residues ( from 32 to 121). The pressure stability is dramatically reduced with decreasing N- domain length and the process is not reversible for rPrP(Delta 51 - 90) and rPrP(Delta 32 - 121), whereas it is completely reversible for the wild- type form. Decompression to atmospheric pressure triggers immediate aggregation for the mutants in contrast to a slow aggregation process for the wild- type, as observed by Fourier- transform infrared spectroscopy. The temperature- induced transition leads to aggregation of all rPrPs, but the unfolding temperature is lower for the rPrP amino- terminal deletion mutants. The higher susceptibility to pressure of the amino- terminal deletion mutants can be explained by a change in hydration and cavity distribution. Taken together, our results show that the amino- terminal region has a pivotal role on the development of prion misfolding and aggregation.