Structural, dynamic properties of key residues in Aβ amyloidogenesis:: Implications of an important role of nanosecond timescale dynamics
Structural, dynamic properties of key residues in Aβ amyloidogenesis:: Implications of an important role of nanosecond timescale dynamics
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DOI：
10.1002/cbic.200700194
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发表时间：
2007-07-23
期刊：
影响因子：
3.2
通讯作者：
Louhivuori, Martti
中科院分区：
文献类型：
--
作者：
Lim, Kwang Hun;Henderson, Ginger L.;Louhivuori, Martti
蛋白质聚集体（淀粉样蛋白）的沉积与许多使人衰弱的疾病有关，包括阿尔茨海默病和帕金森病。[1]已经鉴定了形成致病性淀粉样蛋白的多种多肽。已经证明淀粉样蛋白的一级氨基酸序列以及三级结构是高度多样的。[2]此外，与淀粉样蛋白疾病无关的多肽已显示在体外形成淀粉样蛋白。这些研究表明，淀粉样蛋白的形成是多肽链的一种一般性质。然而，多肽的聚集动力学强烈依赖于序列。[2-5]这表明可能存在促进分子间相互作用并随后促进聚集的关键区域。因此，淀粉样蛋白多肽中聚集倾向序列的鉴定在结构生物学中引起了极大的兴趣。最近，数值算法已经开发出预测的聚集倾向的部分，考虑物理化学参数（疏水性，电荷和二级结构倾向）的个别氨基酸残基。[6，7]这些相对简单的方法已经鉴定了各种淀粉样蛋白形成多肽的淀粉样蛋白生成区域。例如，预测AβACHTUNGTRENNUNG（1-42）肽的两个疏水区域（残基17-21和31-42）具有高聚集倾向，这与Aβ原纤维结构密切相关。[8-11]然而，残基17-21，估计具有比C末端略低的聚集分数，已显示在成核Aβ寡聚化中发挥更关键的作用。[5，12-15]这表明，为了更好地理解聚集倾向，应考虑多肽的其他性质。淀粉样蛋白的形成涉及未折叠和/或部分折叠的单体淀粉样蛋白生成中间体分子间缔合成β结构的不溶性淀粉样蛋白;[1]这使得淀粉样蛋白形成过程在ACHTUNGTRENNUNGentropy变化方面非常不利。因此，具有β折叠特征的更有序的多肽片段可能更易于ACHTUNGTRENNUNG启动和促进淀粉样蛋白形成所必需的分子间缔合。在这项研究中，研究了具有不同聚集倾向的各种形式的Aβ肽的结构和动力学性质，以确定聚集倾向区域是否具有不同的性质。残余偶极耦合（RDC）[16，17]和15 N弛豫NMR实验，提供了关于蛋白质无序状态的宝贵结构信息，[15，18-29]被用来研究结构，Aβ肽的动力学特征.天然未折叠AβACHTUNGTRENNUNG（1-40）的残余局部结构在38 ℃的非淀粉样蛋白生成温度下，在应变凝胶中用RDC测量探索肽[30]（图1A）。通过使用程序PALES [32]，将实验RDC曲线（红色）与统计线圈模型[31]计算的RDC曲线（蓝色）进行比较（图1A）。在N-末端区域观察到实验和计算的RDC曲线之间的良好一致性;这表明局部结构性质是氨基酸序列固有的。然而，残基Tyr 10、Phe 19和Phe 20的RDC值明显偏离估计值。较低的RDC值表明，芳香残基可能有一个转弯的功能，这是观察到在以前的研究无序状态的蛋白质。[26[33]这也是一个有趣的…
The deposition of protein aggregates (amyloid) is associated with numerous debilitating human diseases, including Alzheimer’s and Parkinson’s diseases.[1] A variety of polypeptides that form pathogenic amyloids have been identified. It has been demonstrated that the primary amino-acid sequence as well as tertiary structures of amyloidogenic proteins are highly diverse.[2] In addition, polypeptides that are not related to amyloid diseases have been shown to form amyloids in vitro. These studies indicate that amyloid formation is a generic property of a polypeptide chain. Aggregation kinetics of polypeptides are, however, strongly dependent on the sequence.[2–5] This suggests that there might exist critical regions that facilitate intermolecular interactions and subsequently promote aggregation. Identification of aggregation-prone sequences in amyloidogenic polypeptides has, therefore, been of great interest in structural biology. Recently, numerical algorithms have been developed to predict the aggregation-prone segment by considering physicochemical parameters (hydrophobicity, charge, and secondary-structure propensity) of individual amino-acid residues.[6, 7] Such relatively simple approaches have identified the amyloidogenic regions for various amyloid-forming polypeptides. For example, two hydrophobic regions, residues 17–21 and 31–42, of the AβACHTUNGTRENNUNG (1–42) peptide were predicted to have high aggregation propensities, which correlated well with the Aβ fibril structure.[8–11] However, residues 17–21, which were estimated to have a slightly lower aggregation score than the C terminus, have been shown to play a more critical role in nucleating Aβ oligomerization.[5, 12–15] This indicates that additional properties of a polypeptide should be considered for a better understanding of the aggregation propensity. Amyloid formation involves intermolecular association of unfolded and/or partly folded monomeric amyloidogenic intermediates into β-structured insoluble amyloids;[1] this renders the amyloid-forming process highly unfavorable in terms of ACHTUNGTRENNUNGentropy change. More ordered polypeptide segments with βsheet characteristics might, therefore, be more amenable to ACHTUNGTRENNUNGinitiating and promoting intermolecular associations that are necessary for amyloid formation. In this study, structural, dynamic properties of various forms of Aβ peptides with different aggregation propensities were investigated in order to determine whether aggregation-prone regions posses distinct properties. Residual dipolar couplings (RDC)[16, 17] and 15N relaxation NMR experiments, which have provided invaluable structural information on disordered states of proteins,[15, 18–29] were employed to investigate the structural, dynamic features of Aβ peptides.Residual local structures of the natively unfolded AβACHTUNGTRENNUNG (1–40) peptide were explored with RDC measurement in strained gels at the nonamyloidogenic temperature of 38C [30](Figure 1 A). The experimental RDC profile (red) was compared to that calculated (blue) from a statistical coil model [31] by using the program PALES [32](Figure 1A). A good agreement between the experimental and calculated RDC profiles was observed in the N-terminal region; this suggests that the local structural properties are intrinsic to the amino-acid sequence. RDC values of residues Tyr10, Phe19, and Phe20, however, notably deviated from the estimated values. The lower RDC values suggest that the aromatic residues might have a turn-like feature, which was observed in previous studies of disordered states of proteins.[26, 33, 34] It is also interesting to …