Molecular dynamics studies on the buffalo prion protein

被引:4
|
作者
Zhang, Jiapu [1 ,2 ,3 ]
Wang, Feng [1 ]
Chatterjee, Subhojyoti [1 ]
机构
[1] Swinburne Univ Technol, Mol Model Discovery Lab, Fac Sci Engn & Technol, Dept Chem & Biotechnol, Hawthorn Campus, Hawthorn, Vic 3122, Australia
[2] Federat Univ Australia, Fac Sci, Grad Sch Sci Informat Technol & Engn, Mt Helen Campus, Ballarat, Vic 3353, Australia
[3] Federat Univ Australia, Ctr Informat & Appl Optimisat, Mt Helen Campus, Ballarat, Vic 3353, Australia
来源
关键词
low susceptibility species; molecular dynamics; transmissible spongiform encephalopathies; bovine spongiform encephalopathy; buffalo; prion diseases; NMR STRUCTURE; BETA-2-ALPHA-2; LOOP; GENE PRNP; CATTLE; PROPENSITY; CONVERSION; DIVERSITY; MECHANISM; VARIANTS; DISEASES;
D O I
10.1080/07391102.2015.1052849
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-Straussler-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 (PrPC), predominantly with alpha-helices, into insoluble abnormally folded infectious prions (PrPSc), rich in beta-sheets. In this article, we studied the molecular structure and structural dynamics of buffalo PrPC (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 beta 2-alpha 2 loop linked in buffalo. We also found there is a very strong HB SER170-TYR218 linking this loop with the C-terminal end of alpha-helix H3. Other information, such as (i) there is a very strong SB HIS187-ARG156 (N-O) linking alpha-helices H2 and H1 (if mutation H187R is made at position 187, then the hydrophobic core of PrPC 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 PrPC (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 3(10) helices at 125-127, 152-156, and in the beta 2-alpha 2 loop, respectively, and (iv) in the beta 2-alpha 2 loop, there is a strong pi-pi stacking and a strong pi-cation F175-Y169-R164.(N)NH2, has been discovered.
引用
收藏
页码:762 / 777
页数:16
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