A multistage pathway for human prion protein aggregation in vitro: from multimeric seeds to β-oligomers and nonfibrillar structures.
A multistage pathway for human prion protein aggregation in vitro: from multimeric seeds to β-oligomers and nonfibrillar structures.
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DOI：
10.1021/ja1117446
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发表时间：
2011-06-08
影响因子：
15
通讯作者：
De Yoreo JJ
中科院分区：
文献类型：
--
作者：
Cho KR;Huang Y;Yu S;Yin S;Plomp M;Qiu SR;Lakshminarayanan R;Moradian-Oldak J;Sy MS;De Yoreo JJ
Aberrant protein aggregation causes numerous neurological diseases including Creutzfeldt—Jakob disease (CJD), but the aggregation mechanisms remain poorly understood. Here, we report AFM results on the formation pathways of β-oligomers and nonfibrillar aggregates from wild-type full-length recombinant human prion protein (WT) and an insertion mutant (10OR) with five additional octapeptide repeats linked to familial CJD. Upon partial denaturing, seeds consisting of 3–4 monomers quickly appeared. Oligomers of ∼11–12 monomers then formed through direct interaction of seeds, rather than by subsequent monomer attachment. All larger aggregates formed through association of these β-oligomers. Although both WT and 10OR exhibited identical aggregation mechanisms, the latter oligomerized faster due to lower solubility and, hence, thermodynamic stability. This novel aggregation pathway has implications for prion diseases as well as others caused by protein aggregation.
