Aggregation/Fibrillogenesis of Recombinant Human Prion Protein and Gerstmann-Sträussler-Scheinker Disease Peptides in the Presence of Metal Ions

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• 作者：Fernanda Ricchelli ; Raffaella Buggio ; Denise Drago ; Mario Salmona ; Gianluigi Forloni ; Alessandro Negro ; Giuseppe Tognon ; and Paolo Zatta
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：May 30, 2006
• 年：2006
• 卷：45
• 期：21
• 页码：6724 - 6732
• 全文大小：330K
• 年卷期：v.45,no.21(May 30, 2006)
• ISSN：1520-4995

文摘

In this study we investigated the role of Cu²⁺, Mn²⁺, Zn²⁺, and Al³⁺ in inducing defectiveconformational rearrangements of the recombinant human prion protein (hPrP), which trigger aggregationand fibrillogenesis. The research was extended to the fragment of hPrP spanning residues 82-146, whichwas identified as a major component of the amyloid deposits in the brain of patients affected by Gerstmann-Sträussler-Scheinker (GSS) disease. Variants of the 82-146 wild-type subunit [PrP-(82-146)_wt] werealso examined, including entirely, [PrP-(82-146)_scr], and partially scrambled, [PrP-(82-146)_106-126scr]and [PrP-(82-146)_127-146scr], peptides. Al³⁺ strongly stimulated the conversion of native hPrP into thealtered conformation, and its potency in inducing aggregation was very high. Despite a lower rate andextent of prion protein conversion into altered isoforms, however, Zn²⁺ was more efficient than Al³⁺ inpromoting organization of hPrP aggregates into well-structured, amyloid-like fibrillar filaments, whereasMn²⁺ delayed and Cu²⁺ prevented the process. GSS peptides underwent the fibrillogenesis process muchfaster than the full-length protein. The intrinsic ability of PrP-(82-146)_wt to form fibrillar aggregates wasexalted in the presence of Zn²⁺ and, to a lesser extent, of Al³⁺, whereas Cu²⁺ and Mn²⁺ inhibited theconversion of the peptide into amyloid fibrils. Amino acid substitution in the neurotoxic core (sequence106-126) of the 82-146 fragment reduced its amyloidogenic potential. In this case, the stimulatoryeffect of Zn²⁺ was lower as compared to the wild-type peptide; on the contrary Al³⁺ and Mn²⁺ induceda higher propensity to fibrillation, which was ascribed to different binding modalities to GSS peptides. Inall cases, alteration of the 127-146 sequence strongly inhibited the fibrillogenesis process, thus suggestingthat integrity of the C-terminal region was essential both to confer amyloidogenic properties on GSSpeptides and to activate the stimulatory potential of the metal ions.