Structural characterization of the intrinsically unfolded protein β-synuclein, a natural negative regulator of α-synuclein aggregation
Structural characterization of the intrinsically unfolded protein β-synuclein, a natural negative regulator of α-synuclein aggregation
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DOI：
10.1016/j.jmb.2007.07.009
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发表时间：
2007-09-21
影响因子：
5.6
通讯作者：
Fernandez, Claudio O.
中科院分区：
文献类型：
--
作者：
Bertoncini, Carlos W.;Rasia, Rodolfo M.;Fernandez, Claudio O.
突触核蛋白家族是由三个高度同源的蛋白质组成的。突触核蛋白是神经退行性疾病和癌症的重要成员，包括α-突触核蛋白（α S）、β-突触核蛋白（β S）和γ-突触核蛋白（γ S）。α S在被鉴定为帕金森病和路易体痴呆中淀粉样沉积物的主要蛋白质组分后，已被深入研究。另一方面，OS被发现是α S淀粉样蛋白形成的有效抑制剂，并且被认为是其神经毒性的天然调节剂。然后，它是特别感兴趣的，以阐明β S的可溶性状态的结构和动力学特征作为第一步，以了解其抗淀粉样蛋白生成作用的分子基础上的α S，我们在这里提出的表征天然非结构化β S的高分辨率hetero-NMR技术。脉冲场梯度的组合，三维异质结相关，残留偶极耦合，顺磁弛豫增强和骨干松弛实验的特征由蛋白质的构象填充的合奏。结果表明，β S在其天然状态下采用扩展构象，其特征在于缺乏先前报道的α S的长程接触。尽管缺乏明确的二级结构，我们发现的证据，短暂的聚脯氨酸II构象聚集在C-末端区域。在C末端残基处的骨架结构嵌入富含亲水性和带负电荷的氨基酸的多肽段中。通过与其神经毒性同系物α S的彻底比较，分析了这些发现的结构和功能意义。
The synuclein family of intrinsically unfolded proteins is composed of three highly homologous. members, alpha-synuclein (alpha S), beta-synuclein (beta S) and gamma-synuclein (gamma S), which are linked to neurodegenerative disorders and cancer. alpha S has been studied intensively after its identification as the major protein component of amyloid-like deposits in Parkinson's disease and dementia with Lewy bodies. OS, on the other hand, was found to act as a potent inhibitor of alpha S amyloid formation, and it is proposed as a natural regulator of its neurotoxicity. It is then of particular interest to elucidate the structural and dynamic features of the soluble state of beta S as a first step to understand the molecular basis of its anti-amyloidogenic effect on alpha S We present here the characterization of natively unstructured beta S by high resolution heteronuclear NMR techniques. A combination of pulse-field gradient, three-dimensional heteronuclear correlation, residual dipolar couplings, paramagnetic relaxation enhancement and backbone relaxation experiments were employed to characterize the ensemble of conformations populated by the protein. The results indicate that beta S adopts extended conformations in its native state, characterized by the lack of the long-range contacts as previously reported for alpha S. Despite the lack of defined secondary structure, we found evidence for transient polyproline II conformations clustered at the C-terminal region. The structuring of the backbone at the C terminus residues embedded in a polypeptide stretch rich in hydrophilic and negatively charged amino acids. The structural and functional implications of these findings are analyzed via a thorough comparison with its neurotoxic homolog alpha S.