Prion cellular form

The normal cellular form of prion protein (PrPc) can exist as a Cu-metalloprotein in vivo (492). This PrPc is a precursor of the pathogenic protease-resistant form PrPsc, which is thought to cause scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt—Jakob disease. Two octa-repeats of PHGGGWGQ have been proposed as Cu(II) binding sites centered on histidine (493). They lack secondary and tertiary structure in the absence of Cu(II). Neurons may therefore have special mechanisms to regulate the distribution of copper. 

With the background of the mad cow crisis in Europe, questions relating to the prion diseases have attracted intensive interest. It is now widely accepted that prion diseases, such as Creutzfeldt-Jakob disease (CJd) in humans and bovine spongiform encephalopathy (BSE) are caused by a conformational change of the prion protein (PrP) from a normally folded cellular form, PrP ", to an alternate, aggregation-prone, pathogenic scrapie form,... 

The cellular form of the prion protein, called PrP, is synthesized as a 253 amino acid precursor protein in humans (Figure 29. IB) (Prusiner, 1991). The N-terminal 22 amino acid residues serve as the signal peptide that allows insertion of the nascent PrP peptide into the secretory pathway during biosynthesis. The C-terminal 22 amino acid residues are involved in the covalent addition of the glycosylphosphatidylino-sitol (GPI) moiety to serine at amino acid 231 (i.e., Ser 9-The GPI anchor tethers PrP to the exhacellular side of the plasma membrane. PrP has two N-hnked glycosylation sites (Asn and Asn ) that are the sites of attachment of complex... 

The crucial event in prion diseases involves the conformational change of the cellular form of the prion protein into the pathogenic isoform. This change causes a dramatic alteration within the structure. Structural... 

The protein-only hypothesis indicates that the scrapie form of the prion protein can promote the conversion of the cellular form. This leads to the conclusion that prions themselves can act as chaperones (Liautard, 1991). Thermokinetic analysis of protein folding shows that a misfolded chaperone gives rise to new misfolded chaperones, which fit very well to the protein-only hypothesis in which PrP triggers the formation of PrP. ... 

Prion and scrapie diseases are linked with the conformational transition of normally monomeric a-helical cellular prion protein, PrP, to a B-sheet-rich pathogenic form, PrP , which is prone to aggregation. A similar conformational transition of the normal cellular form of a-helical amyloid peptide (aAP (1-40)) into the disease-specific largely B-sheet form of amyloid peptide (BAP (1-40)) occurs in Alzheimer s disease, which results in amyloid deposits (Monaco et al., 2006). So far more than 19 different mutations in the human PrP gene have been linked with inherited prion diseases (Monaco et al., 2006). However, the molecular event triggering the spontaneous conversion of wild-type and... 

Soto, C. 2006. Prions. The New Biology of Proteins. CRC Press, Boca Raton, USA Stahl, N., Borchelt, D. R., and Prusiner, S. B. 1990. Differential release of cellular and scrapie prion protein form cellular membranes of phosphatidylinositol specific phospholipase. Biochemistry 29 5405-5412... 

A prion protein, designated as PrP, has a natural monomeric form, designated PrP, and an insoluble, phase-separated or associated form, designated PrP , where the superscript C stands for the normal cellular form and the superscript Sc stands for the infectious scrapie form. PrP is degradable by proteoljdic enzymes, whereas PrP , the smaller component of PrP, forms a proteolytic resistant core. 

Prion diseases resulting in encephalopathy can be transmitted between individuals within species (more rarely between species) [26-28], A conformational variant of the normal cellular protein PrPs (PrPc) (protease-sensitive or cellular) is believed to catalyze [29] or nucleate [30-33] conversion to the pathological form, PrPR (protease-resistant). This highly unusual nongenetic mode of transmission of an infectious agent has been strongly debated [29]. The observation of multiple examples of nucleated catalysis of aberrant polymerization of protein subunits has... 

All fungal prion proteins have a so-called prion domain and a functional domain. The prion domain is a region of the polypeptide chain that is necessary and sufficient for prion formation and maintenance (Fig. 1 Wickner et al., 2002). For Ure2p and Sup35p, the functional domain is responsible for the cellular activity of the normal form of the protein. 

A third yeast prion, PIN, is similar in some respects, but its non-prion domain—in this case, the N-terminal part of the molecule—has no established cellular function. The protein Rnqlp is a gain-of-function prion whose activity is expressed via its ability to induce [PS/]. [PIN] forms much more readily than the other two prions, and [PIN] cells induce [PSI] under... 

The prion protein, implicated in diseases such as mad cow and Creutzfeldt-Jakob, is another that has been proposed to undergo extensive refolding to form fibrils. In its native, cellular conformation (PrPc), residues 23-124 are... 

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