Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity
Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity
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DOI：
10.1074/jbc.m111.329763
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发表时间：
2012-07-13
影响因子：
4.8
通讯作者：
Tessier, Peter M.
中科院分区：
文献类型：
--
作者：
Ladiwala, Ali Reza A.;Litt, Jeffrey;Tessier, Peter M.
几种蛋白质构象障碍（帕金森病和朊病毒病）与蛋白质异常折叠成前原纤维寡聚体和淀粉样原纤维有关。虽然预纤维状低聚物比它们的纤维状对应物更有毒性，但是难以分离它们不同毒性的起源，因为低聚物和纤维在结构和尺寸方面都不同。在这里，我们报告的42-残基淀粉样蛋白β（A β 42）肽与阿尔茨海默病，具有相似的大小和不同的毒性的两个低聚物的特性。我们发现，A β 42自发地形成prefibrillar寡聚体在A β浓度低于30 μ M的情况下搅拌，而较高的A β浓度导致快速形成原纤维。有趣的是，A β前原纤低聚物在静止组装条件下不转化为原纤，而是转化为具有与A β前原纤低聚物相似的尺寸和形态的第二种类型的低聚物。引人注目的是，这种替代的A β寡聚体相对于A β单体对哺乳动物细胞无毒。我们发现A β内的两个疏水肽段（残基16-22和30-42）在毒性更强的A β寡聚体中暴露于更多溶剂。毒性较低的寡聚体缺乏β折叠结构，不溶，并且与寡聚体和原纤维特异性抗体无免疫反应性。此外，毒性较小的低聚物不能破坏脂质双层，与其毒性较大的低聚物对应物相反。我们的研究结果表明，非纤维状A β寡聚体与细胞膜相互作用和破坏细胞膜的能力与其中心和C-末端疏水肽段的溶剂暴露程度有关。
Several protein conformational disorders (Parkinson and prion diseases) are linked to aberrant folding of proteins into prefibrillar oligomers and amyloid fibrils. Although prefibrillar oligomers are more toxic than their fibrillar counterparts, it is difficult to decouple the origin of their dissimilar toxicity because oligomers and fibrils differ both in terms of structure and size. Here we report the characterization of two oligomers of the 42-residue amyloid beta (A beta 42) peptide associated with Alzheimer disease that possess similar size and dissimilar toxicity. We find that A beta 42 spontaneously forms prefibrillar oligomers at A beta concentrations below 30 mu M in the absence of agitation, whereas higher A beta concentrations lead to rapid formation of fibrils. Interestingly, A beta prefibrillar oligomers do not convert into fibrils under quiescent assembly conditions but instead convert into a second type of oligomer with size and morphology similar to those of A beta prefibrillar oligomers. Strikingly, this alternative A beta oligomer is non-toxic to mammalian cells relative to A beta monomer. We find that two hydrophobic peptide segments within A beta (residues 16-22 and 30-42) are more solvent-exposed in the more toxic A beta oligomer. The less toxic oligomer is devoid of beta-sheet structure, insoluble, and non-immunoreactive with oligomer-and fibril-specific antibodies. Moreover, the less toxic oligomer is incapable of disrupting lipid bilayers, in contrast to its more toxic oligomeric counterpart. Our results suggest that the ability of non-fibrillar A beta oligomers to interact with and disrupt cellular membranes is linked to the degree of solvent exposure of their central and C-terminal hydrophobic peptide segments.