Intrinsic toxicity of the cellular prion protein is regulated by its conserved central region

The conserved central region (CR) of PrP (c) has been hypothesized to serve as a passive linker connecting the protein's toxic N-terminal and globular C-terminal domains. Yet, deletion of the CR causes neonatal fatality in mice, implying the CR possesses a protective function. The CR encompasses the regulatory alpha-cleavage locus, and additionally facilitates a regulatory metal ion-promoted interaction between the PrP (c) N- and C-terminal domains. To elucidate the role of the CR and determine why CR deletion generates toxicity, we designed PrP (c) constructs wherein either the cis-interaction or alpha-cleavage are selectively prevented. These constructs were interrogated using nuclear magnetic resonance, electrophysiology, and cell viability assays. Our results demonstrate the CR is not a passive linker and the native sequence is crucial for its protective role over the toxic N-terminus, irrespective of alpha-cleavage or the cis-interaction. Additionally, we find that the CR facilitates homodimerization of PrP (c), attenuating the toxicity of the N-terminus.