Molecular dynamics studies of dog prion protein wild-type and its D159N mutant

Abstract

Prion diseases (e.g. 'mad cow' disease in cattle, chronic wasting disease in deer and elk, Creutzfeldt-Jakob disease in humans) have been a major public health concern affecting humans and almost all animals. However, dogs are strongly resistant to prion diseases. Recently, through transgenic techniques, it was reported that the single (surface) residue D159 is sufficient to confer protection against protein conformational change and pathogenesis, thus provides conformational stability for dog prion protein. This made a big breakthrough in dog prion protein research field. For dog prion protein, another advancement is the produce of its NMR structure in 2005. However, all these breakthroughs are still short of enough structural informatics of dog prion protein. This paper studies dog prion protein wild-type and D159N mutant through molecular dynamics (MD) techniques. Our MD results reveal sufficient structural informatics on the residue at position 159 to understand the mechanism underlying the resistance to prion diseases of dogs. The structural informatics of this paper should be very useful for the medicinal treatment of prion diseases.

Arg177 and Asp159 from dog prion protein slow liquid–liquid phase separation and inhibit amyloid formation of human prion protein

“…Because dogs are resistant to prion infection, partly because of the presence of Asp159 in their PrP ( 26 , 27 , 28 , 29 , 30 , 33 , 34 , 35 ), and Asp159 suppresses the toxicity of mouse PrP in Drosophila ( 27 ), we chose to investigate the regulation mechanism of Asp159 on PrP C liquid-phase condensation. We used two mutations at codon 159, bacterial-purified N159D of human PrP C and D159N of dog PrP C , labeled by TAMRA (red fluorescence) and incubated with 1× PBS (pH 7.4) containing 10% (w/v) PEG 8000 on ice.…”

“…Recently, several in vitro and in vivo studies have demonstrated that Asp159 from the dog PrP plays a critical role in encoding higher structural stability of PrP in prion-resistant canids ( 26 , 27 , 28 , 29 , 30 , 33 , 34 , 35 ). Because Arg177 and Asp159 cause unique charge distribution patterns on the front and back sides of dog PrP C , it has generally been thought that these two unique amino acid residues might be responsible for the prion resistance of canids ( 27 , 28 , 29 , 52 , 53 ).…”

“…Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of PrP from α-helix-dominant PrP C to β-sheet-rich PrP Sc in many mammalian species ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ). In contrast to most mammalian species such as humans, a few mammals, including dogs, rabbits, and horses, exhibit resistance to prion diseases and are thus recognized as prion-resistant mammals ( 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ), but the mechanism behind the phenomenon remains unclear. Compared with PrP from most mammals including humans, PrP from dogs has two unique amino acid residues, Arg177 and Asp159, in which Asp159 suppresses the toxicity of mouse PrP in Drosophila ( 27 ) and has been cited as critical for encoding PrP conformational stability in prion-resistant dogs ( 26 , 27 , 28 , 29 , 30 , 33 , 34 , 35 ).…”

“…In contrast to most mammalian species such as humans, a few mammals, including dogs, rabbits, and horses, exhibit resistance to prion diseases and are thus recognized as prion-resistant mammals ( 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ), but the mechanism behind the phenomenon remains unclear. Compared with PrP from most mammals including humans, PrP from dogs has two unique amino acid residues, Arg177 and Asp159, in which Asp159 suppresses the toxicity of mouse PrP in Drosophila ( 27 ) and has been cited as critical for encoding PrP conformational stability in prion-resistant dogs ( 26 , 27 , 28 , 29 , 30 , 33 , 34 , 35 ). However, it is unclear whether Arg177 and Asp159 from the dog PrP regulate amyloid fibril formation of PrP.…”