Molecular dynamics studies on the buffalo prion protein

Abstract

It was reported that buffalo is a low susceptibility species resisting to transmissible spongiform encephalopathies (TSEs) (same as rabbits, horses, and dogs). TSEs, also called prion diseases, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of species (except for rabbits, dogs, horses, and buffalo), manifesting as scrapie in sheep and goats; bovine spongiform encephalopathy (BSE or "mad-cow" disease) in cattle; chronic wasting disease in deer and elk; and Creutzfeldt-Jakob diseases, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and Kulu in humans etc. In molecular structures, these neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrP(C)), predominantly with α-helices, into insoluble abnormally folded infectious prions (PrP(Sc)), rich in β-sheets. In this article, we studied the molecular structure and structural dynamics of buffalo PrP(C) (BufPrP(C)), in order to understand the reason why buffalo is resistant to prion diseases. We first did molecular modeling of a homology structure constructed by one mutation at residue 143 from the NMR structure of bovine and cattle PrP(124-227); immediately we found that for BufPrP(C)(124-227), there are five hydrogen bonds (HBs) at Asn143, but at this position, bovine/cattle do not have such HBs. Same as that of rabbits, dogs, or horses, our molecular dynamics studies also revealed there is a strong salt bridge (SB) ASP178-ARG164 (O-N) keeping the β2-α2 loop linked in buffalo. We also found there is a very strong HB SER170-TYR218 linking this loop with the C-terminal end of α-helix H3. Other information, such as (i) there is a very strong SB HIS187-ARG156 (N-O) linking α-helices H2 and H1 (if mutation H187R is made at position 187, then the hydrophobic core of PrP(C) will be exposed (L.H. Zhong (2010). Exposure of hydrophobic core in human prion protein pathogenic mutant H187R. Journal of Biomolecular Structure and Dynamics 28(3), 355-361)), (ii) at D178, there is a HB Y169-D178 and a polar contact R164-D178 for BufPrP(C) instead of a polar contact Q168-D178 for bovine PrP(C) (C.J. Cheng, & V. Daggett. (2014). Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH. Biomolecules 4(1), 181-201), (iii) BufPrP(C) owns three 310 helices at 125-127, 152-156, and in the β2-α2 loop, respectively, and (iv) in the β2-α2 loop, there is a strong π-π stacking and a strong π-cation F175-Y169-R164.(N)NH2, has been discovered.

A Survey on π-π Stackings and π-Cations in Prion Protein Structures

“…The above bioinformatics might be acted as a "quick reference card" for PrP protein structure π-interaction studies [1,2].…”

Genetic Resistance to Prion Diseases

“…A comparative study revealed that the SPRN gene has species-speciic indel polymorphisms in catle and bufaloes and causes diferent promoter activity and expression levels [144]. Furthermore, according to the results of more recent study, molecular structure of bufalo cellular prion protein is diferent from catle, but similar to those of rabbits, dog and horse which are considered low susceptible to TSEs [145]. These molecular and structural diferences may be another explanation with regard to TSEs resistance in bufaloes.…”

Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review

“…Mammals carrying a flexible β2–α2 loop are easily infected by prions, while in animals carrying a rigid loop, prions are poorly infected [51]. Notably, the horse, rabbit, dog, and buffalo are mammalian species reported as resistant to infection from prion diseases isolated from other species [52,53,54,55].…”

“…The flexibility in the variation facilitates the access to alternate conformational states of the protein, remodeling the sites for molecular recognition events (i.e., protein-protein and protein-ligand interactions) [57]. Molecular dynamics studies have revealed that in rabbits, dogs, horses, and buffalo [52,53,54,55], species resistant to infection from prion diseases, there is a strong salt bridge Asp178-Arg164 (O-N) keeping the β2–α2 loop closely linked and contributing to the structural stability of prion protein. Another recent study about the low prion susceptibility of canids, based on the amino acid sequence of the canine PrP, identified the relevance of the Asp163 amino acid in proneness to protein misfolding, showing it was a key amino acid with characteristics responsible for the high resistance to prion disease [58].…”