Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion

Abstract

Prions are unorthodox pathogens that cause fatal neurodegenerative diseases in humans and other mammals. Prion propagation occurs through the self-templating of the pathogenic conformer PrP Sc , onto the cell-expressed conformer, PrP C . Here we study the conversion of PrP C to PrP Sc using a recombinant mouse PrP Sc conformer (mouse protein-only recPrP Sc ) as a unique tool that can convert bank vole but not mouse PrP C substrates in vitro . Thus, its templating ability is not dependent on sequence homology with the substrate. In the present study, we used chimeric bank vole/mouse PrP C substrates to systematically determine the domain that allows for conversion by Mo protein-only recPrP Sc . Our results show that that either the presence of the bank vole amino acid residues E227 and S230 or the absence of the second N-linked glycan are sufficient to allow PrP C substrates to be converted by Mo protein-only recPrP Sc and several native infectious prion strains. We propose that residues 227 and 230 and the second glycan are part of a C-terminal domain that acts as a linchpin for bank vole and mouse prion conversion.

A single amino acid residue in bank vole prion protein drives permissiveness to Nor98/atypical scrapie and the emergence of multiple strain variants

“…Bank voles are the first wild type rodents showing susceptibility to AS. The peculiar susceptibility of bank voles to a wide range of prion sources has been mainly ascribed to features of vole PrP rather than to the vole genetic background [59,63,68,[81][82][83]. Indeed, the ability of bank voles to faithfully propagate AS was clearly dependent on a single PrP amino acid residue, i.e.…”

Site-specific analysis of N-glycans from different sheep prion strains

“…Although prion conversion is possible without glycans, the importance of investigating glycosylation in strains has been emphasized in a recent study, in which it was shown that strain conformation determines both cofactor and glycosylation preferences, supporting the strain-specific neurotropism hypothesis [ 69 ]. The same group of researchers has also shown in vitro that the second glycosylation site affects prion conversion, suggesting this site has a role in controlling the conversion of PrP Sc to PrP C [ 70 ]. Although studies investigating prion glycosylation have not always been consistent, they have led to the suggestion that the prion strain properties are encoded in the backbone of the protein.…”

A single protective polymorphism in the prion protein blocks cross‐species prion replication in cultured cells

“…Finally, since PrP −/− cells are used a starting point in our system, it is straightforward to test the effects of amino acid changes in PrP, such as G127V, on prion susceptibility. This should help to clarify the molecular determinants that allow BVPrP to function as a universal prion acceptor (Agrimi et al, 2008; Burke, Mark, Walsh, et al, 2020; Kurt et al, 2017; Piening et al, 2006).…”

“…For instance, the G127V substitution in human PrP, which was originally found in individuals seemingly resistant to kuru infection (Mead et al, 2009), provides complete resistance to human prions (Asante et al, 2015). At the other end of the prion susceptibility spectrum, PrP from bank voles (BV) has been shown to function as a near‐universal acceptor of prions, enabling efficient replication of a wide variety of prion strains stemming from several different animal species (Agrimi et al, 2008; Arshad et al, 2020; Burke, Mark, Walsh, et al, 2020; Burke, Walsh, Mark, et al, 2020; Cosseddu et al, 2011; Di Bari et al, 2013; Espinosa et al, 2016; Nonno et al, 2006, 2019; Orru et al, 2015; Piening et al, 2006; Pirisinu et al, 2016; Watts et al, 2014). BVPrP is polymorphic at codon 109, where either a methionine (M) or isoleucine (I) residue can be present (Cartoni et al, 2005).…”