The clustering and spatial arrangement of beta-sheet sequence, but not order, govern alpha-synuclein fibrillogenesis.
The clustering and spatial arrangement of beta-sheet sequence, but not order, govern alpha-synuclein fibrillogenesis.
复制标题
β-折叠序列的聚类和空间排列（而非顺序）控制着 α-突触核蛋白原纤维的形成。
DOI：
10.1021/bi901753h
复制
发表时间：
2010
期刊：
影响因子：
2.9
通讯作者：
Ulmer,TobiasS
中科院分区：
文献类型：
--
作者：
Suk,Jae-Eun;Lokappa,SowmyaBekshe;Ulmer,TobiasS
固有的非结构蛋白α-突触核蛋白(AS)容易错误折叠成细胞毒性的富含β片层的寡聚体和淀粉样纤维，这是帕金森氏病等路易体疾病的基础。一个重要的、公认的纤维形成参数是氨基酸含量，而氨基酸序列分布的影响还不是很清楚。AS的纤维核心包含五个高β-Sheet倾向的区域，称为β1−β5。使用四个氨基酸组成相同但伪泥炭基序重排的变体，我们表明β2−β5序列聚类而不是顺序对于有效的纤维形成是重要的。对于向纤维态发展的分子物种，有序性总是增加的，即序列元素的空间排列变得受限。通过以纤维结构为基础的方式引入二硫键，我们证明了成功的原纤维到纤维的转化取决于高β-Sheet倾向的序列元件的空间排列。此外，二硫键连接的AS二聚体可以迅速燃烧。我们认为，构象搜索的基础是纤维作为核的出现，这是由β-Sheet区域之间的序列间隙和可溶性前纤维低聚物中空间β-Sheet排列的可及范围所引导的。基于淀粉样蛋白纤维的普遍的交叉β-Sheet结构，这些原理有望应用于广泛的淀粉样蛋白。
The intrinsically unstructured protein α-synuclein (aS) is prone to misfold into cytotoxic β-sheet-rich oligomers and amyloid fibrils that underlie the pathogenesis of Lewy body diseases such as Parkinson’s disease. An important, recognized fibrillogenesis parameter is amino acid content, whereas the influence of amino acid sequence distribution is not as well understood. The fibril core of aS encompasses five regions of high β-sheet propensity, termed β1−β5. Using four aS variants with identical amino acid compositions but rearranged pseudorepeat motifs, we show that β2−β5 sequence clustering, but not order, is important for efficient fibrillogenesis. For molecular species progressing toward the fibrillar state, order invariably increases; i.e., the spatial arrangement of sequence elements becomes restricted. By introducing disulfide bonds in a fibril structure-based manner, we demonstrated that a successful protofibril-to-fibril conversion is dependent upon the spatial arrangement of sequence elements of high β-sheet propensity. Moreover, a disulfide-linked aS dimer is shown to fibrillize rapidly. We propose that a conformational search underlies the emergence of a fibrillar aS nucleus that is directed by gaps in sequence between β-sheet regions and the accessible range of spatial β-sheet arrangements in soluble, prefibrillar oligomers. On the basis of the universal cross-β-sheet structure of amyloid fibrils, these principles are expected to apply to a wide range of amyloidogenic proteins.