Thermodynamic characterization for the denatured state of bovine prion protein and the BSE Associated variant E211K

Abstract

Propagation of transmissible spongiform encephalopathies involves the conversion of cellular prion protein, PrPC, into a misfolded oligomeric form, PrPSc. The most common hereditary prion disease is a genetic form of Creutzfeldt-Jakob disease in humans, in which a mutation in the prion gene results in a glutamic acid to lysine substitution at position 200 (E200K) in PrP. In cattle, the analogous amino acid substitution is found at residue 211 (E211K) and has been associated with a case of bovine spongiform encephalopathy. Here, we have compared the secondary structure of E211K to that of wild type using circular dichroism and completed a thermodynamic analysis of the folding of recombinant wild type and E211K variants of the bovine prion protein. The secondary structure of the E211K variant was essentially indistinguishable from that of wild type. The thermodynamic stability of E211K substitution showed a slight destabilization relative to the wild type consistent with results reported for recombinant human prion protein and its mutant E200K. In addition, the E211K variant exhibits a similarly compact denatured state to that of wild type based upon similar m-value and change in heat capacity of unfolding for the proteins. Together these results indicate that residual structure in the denatured state of bPrP is present in both the wild type protein and BSE associated variant E211K. Given this observation, as well as folding similarities reported for other disease associated variants of PrP it is worth consideration that functional aspects of PrP conformation may play a role in the misfolding process.

In‐depth examination of PrP Sc in Holstein cattle carrying the E211K somatic mutation of the bovine prion protein gene ( PRNP )

“…However, E200K‐mutant human PrP exhibited nearly identical features, including flexible regions and backbone structure of human PrP, compared to wild‐type human PrP. Similar to E200K‐mutant human PrP, E211K‐mutant bovine PrP also showed minor differences in thermodynamic characteristics (Hwang & Nicholson, 2018). However, previous studies have reported that the E200K mutation of human PrP could influence impairment of copper‐binding capacity, confer susceptibility to copper and be accompanied by oxidative damage (Canello et al., 2010).…”

Handling of endoscopic equipment after use in the case of a patient with suspected prion disease

“…Prion diseases are a group of deadly neurological diseases due to the improper folding of the cellular prion protein (PrPC) inta a pathogenic form (PrP SC ), mainly in the brain, but also in other tissues [1]. The PrP SC protein may cause incorrect folding of subsequent PrP C proteins and cause various diseases in the same host species [2,3]. Prion diseases affect both humans and various animals.…”

“…These include scrapie and goat scrapie, bovine spongiform encephalopathy, chronic, debilitating deer disease and Creutzfeldt-Jacob disease in humans. These disorders can be sporadic, inherited, or acquired by infection [2].…”