Abstract
Prion proteins (PrPs) are infectious pathogens that cause a group of invariably fatal, neurodegenerative diseases, including Creutzfeldt-Jakob disease, by means of an entirely novel mechanism. They are produced by various species, including reptile, rodent, ruminant and mammals, during normal metabolic processes, but they can be slowly changed into pathogenic isoforms upon contact with other infectious PrP isoforms. This transmission can occur across species barriers. In the present study, phylogram for each PrP sequence was generated by PAUP* 4.0 program using Neighbor-Joining method with 1,000 times bootstrapping process for the phylogenetic analysis. The molecular dynamics (MD) simulations were performed by the SANDER module in the AMBER 7 package using Amber 99 force field. All the simulation process was conducted in the IBM p690 Supercomputing System in Korea Institute of Science and Technology Information. To reduce the calculation time, we used the Generalized Born (GB) model. We compared the sequences and structural characteristics of normal and pathogenic (E200K) human PrPs with those of other reptile, rodent, ruminant and mammalian PrPs. Phylogenetic analysis revealed that, although the turtle PrP sequence is the most distinct of the PrPs analyzed, it nonetheless retains five conserved secondary structural elements that are similar to those found in the mammalian PrPs, suggesting that these elements have important functions in vivo. The RMS deviation between the normal and E200K human PrPs was larger than that between the normal human and bovine PrPs, and all of the beta-sheet structures in human E200K PrP were very stable during MD simulations.
Highlights
Prion proteins (PrPs) are infectious pathogens that cause a group of invariably fatal, neurodegenerative diseases by means of an entirely novel mechanism
Since the pathogenic and normal cellular PrP molecules are alternative structural isoforms of the same peptide, without genetic alteration, molecular dynamics (MD) simulation offers an important tool in prion studies
We determined the differences of the primary PrP sequences from 8 different species prior to the MD simulation first, using multiple sequence alignment and phylogenetic analysis techniques
Summary
Prion proteins (PrPs) are infectious pathogens that cause a group of invariably fatal, neurodegenerative diseases by means of an entirely novel mechanism. The disease-causing isoform (PrPSc) reproduces by recruiting and stimulating structural changes in the normal, cellular isoform (PrPC). Qin et al (2002) suggested that it participates in cellular uptake or efflux of extracellular ligands, and might interact with copper ions. PrP binds copper with low-micromolar affinity and in a pH-sensitive manner via N-terminal histidine-containing octapeptide repeats (Jackson et al, 2001; Kramer et al, 2001; Burns et al, 2002). Binding of Cu++ to the C-terminal portion of PrP in vivo seems unlikely, but it has been suggested by experiments using amino-terminal truncations of the protein (Burns et al, 2003)
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