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

Abstract

Prion protein (PrP) gene encodes cellular PrP (PrPC), a glycosylphosphatidylinositol (GPI)-anchored cell membrane protein indispensable for infections of prion, which causes Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. Although PrPC is known to be converted into an abnormal isoform (PrPSc) upon prion infection and play an important role in prion diseases, the mechanisms involved remain unclear, partly due to the insolubility of PrPSc, which prevents experimental biochemical and biophysical analyses. Recently, with improvements in computer power and methods, computer analyses have been contributing more to prion studies. A comparison of PrP gene sequences revealed mutations and polymorphisms in the open reading frame (ORF) of the human PrP gene related to prion diseases. In contrast, little mutations or polymorphisms related to susceptibility to BSE were found in the ORF of the bovine PrP gene, though relationships between insertion/deletion (Ins/Del) polymorphisms of the PrP gene promoter and susceptibility to BSE have been found. Our results have shown that the specific protein 1 (Sp1) plays important role in the activity of PrP gene promoter, which is influenced by polymorphisms in the Sp1 binding sites. The potential structural dynamics of PrP have been simulated by computational methods such as molecular dynamics (MD) and quantum mechanics (QM). The proposed mechanisms of conversion have revealed new insights in prion diseases. In this review, we will introduce the gene structure, polymorphisms, and potential structural dynamics of PrP revealed by basic and advanced computational analyses. The possible contribution of these methods to elucidation of the pathogenicity of prion diseases and functions of PrPC is discussed.

The 5′ Flanking Region and Intron1 of the Bovine Prion Protein Gene (PRNP) Are Responsible for Negative Feedback Regulation of the Prion Protein

“…Candidate transcription activators that may bind to binding sites identified in exon 1 include Sp1, AP-2, and C/EBPα. The expression of many genes is regulated by elements within exon 1 [19], [20], one report shows that exon 1 may also be involved in PRNP regulation [15]. Proteins binding within the exon 1 region repress transcription of the PRNP promoter.…”

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).…”

Discriminant analysis of prion sequences for prediction of susceptibility

“…5 Prion protein (PrP) is encoded by the PrP gene ( PRNP ) and is strongly conserved among mammals. 6 PrP C is a protein of 210 amino acids in length that resides mainly on the surface of the mammalian neuronal cells through C-terminal glycosylphosphatidyl inositol anchors, although it is also expressed in other cell types. 7 Nuclear magnetic resonance spectroscopy has indicated that the C-terminal region of PrP C forms a highly structured globular domain and the N-terminal region forms a non-structured flexible tail.…”

“…9 Sequence variation in the PrP gene appears to be important, as it changes the susceptibility to prion disease. 6, 10 Moreover, the M129V polymorphism of human PrP affects resistance to sporadic CJD. 11 The E219K polymorphism is not found in sCJD patients, suggesting resistance to sCJD.…”

“…6 Various studies of the relevance of conformational changes associated with amino-acid substitutions, amyloid propensity and PRNP genetic variability with prion-disease susceptibility have been conducted using bioinformatics methods, including molecular dynamics and other computational science algorithms. 10, 22, 23 There have been a number of studies regarding PrP polymorphisms that influence the susceptibility to prion disease, leading to the possibility of discrimination of prion-disease susceptibility based only on the primary structure information of PrP without requiring complicated structural analysis.…”