Compared with the X-Ray Structure and Dynamics of Rabbits

Abstract

Prion diseases , traditionally referred to as TSEs, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of mammalian species, manifesting as scrapie in sheep and goats, BSE or ‘mad-cow’ disease in cattle, CWD in deer and elk, and CJDs, GSS, FFI, and kulu in humans, etc. These neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrP C ) into insoluble abnormally folded infectious prions (PrP Sc ), and the conversion of PrPC to PrPSc is believed to involve conformational change from a predominantly α-helical protein to one rich in β-sheet structure. Such a conformational change may be amenable to study by MD techniques. For rabbits, classical studies show they have a low susceptibility to be infected by PrP Sc , but recently it was reported that rabbit prions can be generated through saPMCA (serial automated Protein Misfolding Cyclic Amplification) in vitro and the rabbit prion is infectious and transmissible. In this chapter, we first do a detailed survey on the research advances of rabbit prion protein (RaPrP) and then we perform MD simulations on the X-ray molecular structures of rabbit prion protein wild-type and mutants . The survey shows to us that rabbits were not challenged directly in vivo with other known prion strains and the saPMCA result did not pass the test of the known BSE strain of cattle. Thus, we might still look rabbits as a prion resistant species. MD results indicate that the three α-helices of the wild-type are stable under the neutral pH environment (but under low pH environment the three α-helices have been unfolded into β-sheets), and the three α-helices of the mutants (S170N, S174N, S170N & S174N, I214V) are unfolded into rich β-sheet structures under the same pH environment. In addition, we found an interesting result that the SBs such as ASP201–ARG155 , ASP177–ARG163 contribute greatly to the structural stability of RaPrP.