Cellular form of prion

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. 

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... 

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... 

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. 

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,... 

Defining the mechanisms underlying the generation of PrP from PrP has become one of the central issues in prion research. To address this issue, it is necessary to understand something about the biosynthesis and cellular processing of both forms of PrP. This chapter reviews this subject, focusing first on PrP and then on PrP . ... 

Fig. 6. Model of the cellular pathways involved in generation of PrP. In the infectious manifestation of prion diseases, extracellular PrP in the form of a prion particle (1) interacts with PrP on the cell surface, possibly in detergent-resistant rafts, catalyzing its conversion to PrP (2). Conversion may also occur after uptake of the proteins into an endosomal compartment (3). Once formed, some PrP c accumulates in lysosomes (4), although the protein is probably found in a number of other cellular locations as well. In familial prion disorders, mutant PrP is converted spontaneously to the PrP state via a series of biochemical intermediates, the earliest of which is a PIPLC-resistant form generated in the ER (5). Mutant PrP molecules are subsequently delivered to the cell surface, where they become detergent-insoluble (6) and then protease-resistant (7), possibly in raft domains. Steps 6 and 7 could also occur in endocytic organelles. (Reprinted with permission from Harris, 1999).

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. ... 

Hay, B., Prusiner, S.B., and Lingappa, V.R. (1987b). Evidence for a secretory form of the cellular prion protein. Biochemistry 26, 8110-8115. 

The combined term prion protein (PrP) refers to tbe protein ratber than tbe infectious agent. However, it is increasingly apparent tbat PrP exists in a wide variety of forms tbat are normal (e.g., PrP -), TSE-associated (e.g., PrP , PrPflJ, PrP ), neither (e.g., various recombinant and/or mutated versions of tbe PrP structure), or both. This structural diversity complicates the use of Prusiner s original terms PrP " (cellular PrP) and PrP (scrapie PrP). These terms are still useful under many circumstances, but often need further, more operational and/or functional qualification as the sophistication of current studies increases. Eor instance, since protease resistance is most commonly used to discriminate normal and TSE-associated forms of PrP, the operational terms PrP-sen (protease-sensitive PrP) and PrP-res (protease-... 

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