Folding stability of amyloid- (cid:1) 40 monomer is an important determinant of the nucleation kinetics in fibrillization
Folding stability of amyloid- (cid:1) 40 monomer is an important determinant of the nucleation kinetics in fibrillization
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淀粉样蛋白- (cid:1) 40 单体的折叠稳定性是“brillization”中成核动力学的重要决定因素
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Yun
中科院分区：
文献类型：
--
作者：
Chun;Hoi;Hui‐Ming Yu;Yun‐Chorng Chang;Yun
淀粉样蛋白的形成是由蛋白质错误折叠引发的，随后是自我缔合，最终形成淀粉样蛋白原纤维。在许多淀粉样变性病中发现的有毒前纤维寡聚体强调了理解这种聚集之前的折叠机制的重要性。在这里，我们研究了阿尔茨海默病（AD）中天然未折叠的淀粉样蛋白（cid：1）（A（cid：1））肽和家族变体（A21 G，E22 Q，E22 G，E22 K和D23 N）的折叠特性。在天然电泳，分析超离心，荧光发射，远紫外圆二色性的组合，我们发现，所有A（cid：1）40变体主要是单体的类似残留的二级结构，但不同的疏水暴露的蛋白质表面。在三氟乙醇（TFE）存在和不存在的情况下，盐酸胍（GdnHCl）变性结果表明，A（cid：1）突变体均采用表观的两态平衡模型，但稳定性不同，其中野生型的稳定性低于A21 G，而高于D23 N和E22突变体。通过将折叠稳定性与纤维化中的成核阶段相关联，我们发现变体越稳定，成核就越慢，但D23 N除外。此外，A（cid：1）构象的解折叠导致成熟纤丝的形成减少，但非纤丝、无定形类型的聚集体增加。总之，我们证明了A（cid：1）的折叠稳定性是成核动力学的重要决定因素。Ni，C.- L.，Shi，H.- P.，余，H.- M.，张，Y.- C.的方法，Chen，Y.- R.淀粉样蛋白-（cid：1）40单体的折叠稳定性是成核动力学的重要决定因素。FASEB J.25，1390-1401（2011）。www.fasebj.org
Amyloid formation is initiated by protein misfolding, followed by self-association to ultimately form amyloid fibrils. The discovery of toxic prefibrillar oligomers in many amyloidosis underscores the importance of understanding the folding mechanism prior to such aggregation. Here, we investigated the folding properties of the natively unfolded amyloid- (cid:1) (A (cid:1) ) peptide and the familial variants (A21G, E22Q, E22G, E22K, and D23N) in Alzheimer’s disease (AD). In combinations of native electrophoresis, analytical ultracentrifugation, fluorescence emission, and far-UV circular dichroism, we showed that all A (cid:1) 40 variants are predominantly monomeric with similar residual secondary structures, but distinct hydrophobic-exposed protein surfaces. Guanidine hydrochloride (GdnHCl) denaturation in the absence and presence of trifluoro-ethanol (TFE) showed that A (cid:1) variants adopt an apparent 2-state equilibrium model with different stabilities, in which wild type is less stable than A21G but more stable than D23N and E22 mutants. By correlating the folding stability with the nucleation phase in fibrillization, we found the more stable the variant, the slower the nucleation, except for D23N. Besides, the unfolding of A (cid:1) conformation leads to reduced formation of mature fibrils, but an increase in nonfibrillar, amorphous type of aggregates. Overall, we demonstrated that folding stability of A (cid:1) is an important determinant of the nucleation kinetics.—Ni, C.-L., Shi, H.-P., Yu, H.-M., Chang, Y.-C., and Chen, Y.-R. Folding stability of amyloid- (cid:1) 40 monomer is an important determinant of the nucleation kinetics in fibrillization. FASEB J. 25, 1390–1401 (2011). www.fasebj.org
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影响因子：
5.6
作者：
Yang, Mingfeng;Teplow, David B.
通讯作者：
Teplow, David B.
影响因子：
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作者：
K. Kamino;H. T. Orr;H. Payami;Ellen M. Wijsman;M. E. Alonso;Stefan M. Pulst;L. Anderson;Sheldon O'dahl;E. Nemens;June A. White;A. Sadovnick;Melvyn J. Ball;J. Kaye;Andrew Warren;Melvin G. McInnis;S. Antonarakis;Julie R. Korenberg;V. Sharma;W. Kukull;Eric Larson;Leonard L. Heston;George M. Martin;Thomas D. Bird;G. D. Schellenberg
通讯作者：
K. Kamino;H. T. Orr;H. Payami;Ellen M. Wijsman;M. E. Alonso;Stefan M. Pulst;L. Anderson;Sheldon O'dahl;E. Nemens;June A. White;A. Sadovnick;Melvyn J. Ball;J. Kaye;Andrew Warren;Melvin G. McInnis;S. Antonarakis;Julie R. Korenberg;V. Sharma;W. Kukull;Eric Larson;Leonard L. Heston;George M. Martin;Thomas D. Bird;G. D. Schellenberg
爱荷华突变型β-淀粉样原纤维中新型β-折叠结构的证据。
影响因子：
2.9
作者：
Tycko,Robert;Sciarretta,KimberlyL;Orgel,JosephPRO;Meredith,StephenC
通讯作者：
Meredith,StephenC
影响因子：
5.6
作者：
Krone, Mary Griffin;Baumketner, Andrij;Shea, Joan-Emma
通讯作者：
Shea, Joan-Emma
影响因子：
5.6
作者：
Williams, AD;Portelius, E;Wetzel, R
通讯作者：
Wetzel, R