Secondary structure conversions of Alzheimer's Aβ(1-40) peptide induced by membrane-mimicking detergents
Secondary structure conversions of Alzheimer's Aβ(1-40) peptide induced by membrane-mimicking detergents
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DOI：
10.1111/j.1742-4658.2008.06643.x
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发表时间：
2008-10-01
期刊：
影响因子：
5.4
通讯作者：
Graslund, Astrid
中科院分区：
文献类型：
--
作者：
Wahlstrom, Anna;Hugonin, Loic;Graslund, Astrid
淀粉样蛋白β肽（A β）具有39-42个残基，是在阿尔茨海默病患者大脑中发现的淀粉样斑块的主要成分，可溶性寡聚肽聚集体介导对神经元的毒性作用。A β聚集涉及肽结构向β -片的构象变化。在本研究中，我们报道了洗涤剂对A β结构转变的影响，以模拟生物膜可能具有的作用。在体外，单体A β(1-40)在稀水溶液中呈弱结构。通过逐渐向稀水溶液中加入少量十二烷基硫酸钠（SDS）或十二烷基硫酸锂，在3℃和20℃时CD观察到β(1-40)转化为β片。滴定中的近似等向色点表明，转变主要是一个双态过程。在十二烷基硫酸盐浓度下，β(1-40)几乎失去了所有的核磁共振信号，从而产生最佳的β片含量（近似洗涤剂/肽比= 20）。在这些条件下，硫黄素T荧光测量显示最大的聚集淀粉样结构。核磁共振信号的丢失表明它们也参与了中间化学交换。横向弛豫优化波谱核磁共振谱表明，c端残基比其他残基更具动力学。进一步加入SDS或十二烷基硫酸锂，使其浓度接近临界胶束浓度，CD、NMR和FTIR光谱表明，肽重新排列形成具有α -螺旋段的胶束结合结构，类似于直接向肽溶液中加入高浓度洗涤剂时形成的二级结构。
The amyloid beta peptide (A beta) with 39-42 residues is the major component of amyloid plaques found in brains of Alzheimer's disease patients, and soluble oligomeric peptide aggregates mediate toxic effects on neurons. The A beta aggregation involves a conformational change of the peptide structure to beta-sheet. In the present study, we report on the effect of detergents on the structure transitions of A beta, to mimic the effects that biomembranes may have. In vitro, monomeric A beta(1-40) in a dilute aqueous solution is weakly structured. By gradually adding small amounts of sodium dodecyl sulfate (SDS) or lithium dodecyl sulfate to a dilute aqueous solution, A beta(1-40) is converted to beta-sheet, as observed by CD at 3 degrees C and 20 degrees C. The transition is mainly a two-state process, as revealed by approximately isodichroic points in the titrations. A beta(1-40) loses almost all NMR signals at dodecyl sulfate concentrations giving rise to the optimal beta-sheet content (approximate detergent/peptide ratio = 20). Under these conditions, thioflavin T fluorescence measurements indicate a maximum of aggregated amyloid-like structures. The loss of NMR signals suggests that these are also involved in intermediate chemical exchange. Transverse relaxation optimized spectroscopy NMR spectra indicate that the C-terminal residues are more dynamic than the others. By further addition of SDS or lithium dodecyl sulfate reaching concentrations close to the critical micellar concentration, CD, NMR and FTIR spectra show that the peptide rearranges to form a micelle-bound structure with alpha-helical segments, similar to the secondary structures formed when a high concentration of detergent is added directly to the peptide solution.