Effect of pseudorepeat rearrangement on alpha-synuclein misfolding, vesicle binding, and micelle binding.
Effect of pseudorepeat rearrangement on alpha-synuclein misfolding, vesicle binding, and micelle binding.
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DOI：
10.1016/j.jmb.2009.05.058
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发表时间：
2009-07-17
影响因子：
5.6
通讯作者：
Ulmer, Tobias S.
中科院分区：
文献类型：
--
作者：
Rao, Jampani Nageswara;Kim, Yujin E.;Park, Leena S.;Ulmer, Tobias S.
α-突触核蛋白的病理学和生理学特征分别是其错误折叠成细胞毒性聚集体以及与突触小泡的结合。这两个事件都是由七个 11 残基两亲性假重复序列介导的，并且最一般地涉及从本质上非结构化构象到结构化构象的转变。基于 α-突触核蛋白与聚集抑制小分子的相互作用，引入了一种称为 SaS 的 α-突触核蛋白变体，其中前六个假重复已被重新排列。在这里，参照α-和β-突触核蛋白检查这种重排对错误折叠、囊泡结合和胶束结合的影响，以研究这些过程背后的序列特征。原纤维化与具有高 β-折叠倾向的残基的独特聚类相关，而囊泡亲和力取决于假重复互换和丢失的模式。在胶束存在的情况下，SaS 的假重复区域采用基本上连续的螺旋，而 α- 和 β-突触核蛋白遇到明显的螺旋断裂，表明 SaS 中表面活性剂亲和力的更均匀分布阻止了胶束结合状态下螺旋断裂的形成。通过证明 β-折叠倾向分布的重要性以及揭示不均匀的 aS 表面活性剂亲和力，本研究为突触核蛋白生物学的两个中心主题提供了新的见解。
The pathological and physiological hallmarks of the protein α-synuclein are its misfolding into cytotoxic aggregates and its binding to synaptic vesicles, respectively. Both events are mediated by seven 11-residue amphiphilic pseudorepeats and, most generally, involve a transition from intrinsically unstructured to structured conformations. Based upon α-synuclein interactions with aggregation-inhibiting small molecules, a α-synuclein variant termed SaS, wherein the first six pseudorepeats had been rearranged, was introduced. Here, the effects of this rearrangement upon misfolding, vesicle binding and micelle binding are examined in reference to α- and β-synuclein to study the sequence characteristics underlying these processes. Fibrillization correlates with the distinct clustering of residues with high β-sheet propensities, while vesicle affinities depend on the mode of pseudorepeat interchange and loss. In the presence of micelles, the pseudorepeat region of SaS adopts an essentially continuous helix, whereas α- and β-synuclein encounter a distinct helix break, indicating that a more homogeneous distribution of surfactant affinities in SaS prevented the formation of a helix break in the micelle-bound state. By demonstrating the importance of the distribution of β-sheet propensities and by revealing inhomogeneous aS surfactant affinities, the present study provides novel insight into two central themes of synuclein biology.
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DOI：
10.1073/pnas.0407146102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Bertoncini, CW;Jung, YS;Zweckstetter, M
通讯作者：
Zweckstetter, M
影响因子：
2.7
作者：
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影响因子：
16.8
作者：
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影响因子：
2.9
作者：
Bisaglia, M;Schievano, E;Mammi, S
通讯作者：
Mammi, S
影响因子：
3.4
作者：
Ballesteros, JA;Deupi, X;Pardo, L
通讯作者：
Pardo, L