Abstract
Scrapie prion, PrPSc, formation is the central event of all types of transmissible spongiform encephalopathies (TSEs), while the pathway with possible intermediates and their mechanism of formation from the normal isoform of prion (PrP), remains not fully understood. Recently, the G127V variant of the human PrP is reported to render the protein refractory to transmission of TSEs, via a yet unknown mechanism. Molecular dynamics studies suggested that this mutation interferes with the formation of PrP dimers. Here we analyze the dimerization of 127G and 127VPrP, in both in vitro and a mammalian cell culture system. Our results show that while molecular dynamics may capture the features affecting dimerization in vitro, G127V inhibiting dimer formation of PrP, these are not evidenced in a more complex cellular system.
Highlights
Scrapie prion, PrPSc, formation is the central event of all types of transmissible spongiform encephalopathies (TSEs), while the pathway with possible intermediates and their mechanism of formation from the normal isoform of prion (PrP), remains not fully understood
The formation of a dimer by the bacterially expressed recombinant mouse prion protein has been demonstrated and the dimer interface has been mapped in our earlier w ork[61] by using a genetically incorporated unnatural amino acid, pBpa, that crosslinks to C-H groups of the protein backbone and side chains of nearby proteins situated within a distance of less than 3.1 Å, when irradiated by UV light
Molecular dynamics studies suggest that Tyr[127] (128 in the human prion protein) has a key role in dimer formation and altering the 126Gly to Val changes the orientation of the Tyr side chain, while diminishing PrP dimerization
Summary
Scrapie prion, PrPSc, formation is the central event of all types of transmissible spongiform encephalopathies (TSEs), while the pathway with possible intermediates and their mechanism of formation from the normal isoform of prion (PrP), remains not fully understood. TSEs typically occur spontaneously or due to transmission by diseased individuals and less often due to inherited mutation in the PRNP gene that encodes for the prion protein All these conditions are caused by the conformational conversion of the normal cellular prion protein (PrPC), a cell surface glycosylphosphatidylinositol (GPI) anchored membrane protein, to a protease-resistant, insoluble scrapie conformation (PrPSc) with increased β-sheet content. In order to understand this process, a number of efforts have been made to develop conversion reactions, employing either brain-derived mammalian P rPC or bacterially expressed recombinant PrP These recapitulated several features of the conversion, such as the proteinase K (PK)-resistance of the infectious material or the necessary co-factors, Scientific Reports | (2021) 11:3116
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