Contribution of two conserved glycine residues to fibrillogenesis of the 106-126 prion protein fragment. Evidence that a soluble variant of the 106-126 peptide is neurotoxic

被引:58
作者
Florio, T
Paludi, D
Villa, V
Principe, DR
Corsaro, A
Millo, E
Damonte, G
D'Arrigo, C
Russo, C
Schettini, G
Aceto, A
机构
[1] Univ G DAnnunzio, Dipartimento Sci Biomed, Biochem Sect, I-66100 Chieti, Italy
[2] Univ Genoa, Dept Oncol Biol & Genet, Pharmacol Sect, Genoa, Italy
[3] Adv Biotechnol Ctr, Natl Inst Canc Res, Genoa, Italy
[4] Univ G DAnnunzio, Dept Sci Farm, I-66100 Chieti, Italy
[5] Univ Genoa, Dept Expt Med, Genoa, Italy
[6] CNR, Natl Inst Canc Res, Inst Study Macromol, Div Expt Oncol, Genoa, Italy
关键词
fibrillogenesis; neurotoxicity; prion protein;
D O I
10.1046/j.1471-4159.2003.01664.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The fibrillogenic peptide corresponding to the residues 106-126 of the prion protein sequence (PrP 106-126) is largely used to explore the neurotoxic mechanisms underlying the prion disease. However, whether the neuronal toxicity of PrP 106-126 is caused by a soluble or fibrillar form of this peptide is still unknown. The aim of this study was to correlate the structural state of this peptide with its neurotoxicity. Here we show that the two conserved Gly114 and Gly119 residues, in force of their intrinsic flexibility, prevent the peptide assuming a structured conformation, favouring its aggregation in amyloid fibrils. The substitution of both Gly114 and Gly119 with alanine residues (PrP 106-126 AA mutated peptide) reduces the flexibility of this prion fragment and results in a soluble, beta-structured peptide. Moreover, PrP 106-126 AA fragment was highly toxic when incubated with neuroblastoma cells, likely behaving as a neurotoxic protofibrillar intermediate of the wild-type PrP 106-126. These data further confirm that the fibrillar aggregation is not necessary for the induction of the toxic effects of PrP 106-126.
引用
收藏
页码:62 / 72
页数:11
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