In silico Comparative Analysis of DNA and Amino Acid Sequences for Prion Protein Gene

Abstract

Genetic variability might contribute to species specificity of prion diseases in various organisms. In this study, structures of the prion protein gene (PRNP) and its amino acids were compared among species of which sequence data were available. Comparisons of PRNP DNA sequences among 12 species including human, chimpanzee, monkey, bovine, ovine, dog, mouse, rat, wallaby, opossum, chicken and zebrafish allowed us to identify candidate regulatory regions in intron 1 and 3'-untranslated region (UTR) in addition to the coding region. Highly conserved putative binding sites for transcription factors, such as heat shock factor 2 (HSF2) and myocite enhancer factor 2 (MEF2), were discovered in the intron 1. In 3'-UTR, the functional sequence (ATTAAA) for nucleus-specific polyadenylation was found in all the analysed species. The functional sequence (TTTTTAT) for maturation-specific polyadenylation was identically observed only in ovine, and one or two nucleotide mismatches in the other species. A comparison of the amino acid sequences in 53 species revealed a large sequence identity. Especially the octapeptide repeat region was observed in all the species but frog and zebrafish. Functional changes and susceptibility to prion diseases with various isoforms of prion protein could be caused by numeric variability and conformational changes discovered in the repeat sequences.

Physiological Functions of the Cellular Prion Protein

“…Although PRNP has a short GC-rich region immediately upstream of its transcription start site, as well as other features common to housekeeping genes (Puckett et al, 1991; Sakudo et al, 2010), intron 1 and the sequences upstream of the transcription start site also contain evolutionarily conserved, putative binding sites for numerous transcription factors, including Sp1 (Basler et al, 1986), activator proteins 1 and 2 (Mahal et al, 2001), forkhead box protein O3 (Liu et al, 2013), regulatory factor X1, heat shock factor 2, GATA-binding factor 3, thyrotrophic embryonic factor, myocyte enhancer factor 2, ecotropic viral integration site 1, E4 promoter-binding protein, 4 and nuclear matrix protein 4/cas-interacting zinc finger protein (Kim et al, 2008). These regulatory sequences presumably enable dynamic control of PrP C expression in response to various stimuli, for example, treatment of cultured cells with nerve growth factor, insulin or insulin-like growth factor induces PrP C expression (Kuwahara et al, 2000; Zawlik et al, 2006; Liu et al, 2013).…”

“…The N-terminal domain also contains four tandem repeats of a sequence of eight amino acids, a region of PrP C that is missing in Dpl. These octapeptide repeats may be functionally significant since analysis of PrP C sequences from 53 species showed excellent conservation (Kim et al, 2008). A hydrophobic section (approximately residues 112–133) spans the divide between the N- and C-terminal domains and may be involved in PrP C dimerisation (Rambold et al, 2008; Beland and Roucou, 2013).…”

A national survey on the allelic, genotypic, and haplotypic distribution of PRNP insertion and deletion polymorphisms in Korean cattle

“…The genetic resistance to prion diseases is believed to be an important factor in preventing disease recurrence (Goldmann 2008). Previous research indicates that the PRNP gene encoding the prion protein is present in all vertebrates (Premzl and Gamulin 2007;Kim et al 2008), and that its polymorphisms were associated with susceptibility of prion diseases in humans (Palmer et al 1991), sheep (Belt et al 1995), goat (Billinis et al 2002), deer (O'Rourke et al 2004) and mice (Westaway et al 1994). Much effort has been devoted to establish the association between PRNP and BSE susceptibility in cattle over the last decade (Premzl et al 2000;Walawski and Czarnik 2003).…”

Structure of the Prion Protein and Its Gene: An Analysis Using Bioinformatics and Computer Simulation

“…The entire ORF of all known mammalian PrP genes resides within a single exon, the last exon. Representative features of the gene include: (i) The ORF is not interrupted by introns; (ii) The region immediately 5' of the transcriptional initiating site contains a short GC-rich stretch, which is common in housekeeping genes [12] and might impose stability on the overall secondary structure of PrP mRNA with consequences for its metabolism and translation as in viruses [13]; and (iii) The 3'-untranslated region of mRNA contains highly conserved areas including a functional sequence (ATTAAA) for nucleus-specific polyadenylation [14]; (iv) Intron1 contains putative binding sites for transcription factors such as heat shock factor 2 (HSF2), myocyte enhancer factor 2 (MEF2), E4 promoter-binding protein 4 (E4BP4), nuclear matrix protein 4/cas-interacting zinc finger protein (NMP4/CIZ), regulatory factor X1 (RFX1), thyrotrophic embryonic factor (TEF), and ecotropic viral integration site (EVI1) [14].…”