Regular ArticlePrion protein (PrP) is a cell-surface glycoprotein implicated in the pathogenesis of a range of neurodegenerative disorders collectively termed transmissible spongiform encephalopathies (TSEs), including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cows, and chronic wasting disease (CWD) in deer.1-4) PrP exists in two distinct forms: cellular PrP (PrP C ) and a pathogenic or scrapie form (PrP Sc ) derived from PrP C . Although there is no difference in the primary structure of these isoforms, spectroscopic studies revealed that PrP C has a high ahelical content, whereas PrP Sc is composed primarily of bsheets. 5,6) There are many hypotheses regarding the conversion of PrP C to PrP Sc , but the data suggest that conversion is entirely conformational and involves no amino acid substitutions or deletions, and thus supports the protein-only hypothesis.2) Prion replication requires the conversion of PrP C into PrP Sc , where PrP Sc acts as a template and protein X functions as a chaperone. [7][8][9] Mature human PrP (hPrP) consists of 253 amino acids, with a C-terminal glycosylphosphatidylinositol (GPI) anchor and two glycosylation sites (Fig. 1). The N-terminal domain, which includes four repeats of the PHGGGWGQ octapeptide, is a flexibly disordered region. In contrast, the C-terminal domain, which includes two a-helices and a GPI anchor, is a folded region. The middle domain includes two b-sheets and one a-helix.10-12) The hPrP region spanning amino acid residues 106-126 in the middle domain is thought to be responsible for the pathogenic properties of PrP Sc , including neurotoxicity, protease-resistance, induction of hypertrophy, and promotion of astrocyte proliferation. [13][14][15][16][17] Although PrP metal-binding sites have been investigated using full-length PrP C or synthetic fragment peptides and it is now generally accepted that PrP C binds copper in vivo, 18) most researchers have focused on the octarepeat region, [19][20][21][22][23] and there are few reports describing the metal-binding ability of the middle-and C-terminal domains of hPrP.24) The interaction of full-length and truncated forms of PrP with Cu 2+ has been investigated using a range of techniques, including electron paramagnetic resonance (EPR), [25][26][27] We developed a column switch (CS)-HPLC system that can detect direct metal-binding to the octarepeat region of hPrP C , and the data obtained using our CS-HPLC method agreed well with previous CD analyses. 42,43) In this study, we used CS-HPLC to analyze the metal-binding characteristics of 21 synthetic fragment peptides derived from the sequence of hPrP amino acids 60-230. Key words prion protein; metal-binding; metal chelate affinity column; column switch HPLC; synthetic peptide Chem. Pharm. Bull. 59(8) 965-971 (2011)
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