Sequence determinants regulating fibrillation of human α-synuclein
Sequence determinants regulating fibrillation of human α-synuclein
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DOI：
10.1016/j.bbrc.2008.01.140
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发表时间：
2008-04-11
影响因子：
3.1
通讯作者：
Im, Hana
中科院分区：
文献类型：
--
作者：
Koo, Hyun-Jung;Lee, Hak-Joo;Im, Hana
突触核蛋白是一种神经蛋白，包含路易小体的纤维核心，路易小体是帕金森病的组织学定义病变。为了研究α -突触核蛋白分子中每个特定残基在纤维形成中的作用，在整个分子中引入了氨基酸取代。脯氨酸的掺入，特别是在横跨37-89残基的区域，大大延缓了原纤维的形成。极性残基取代表明，中心疏水区的疏水性在纤颤调节中也很重要。在n端重复区，负电荷数量的增加干扰了纤颤。相比之下，α -突触核蛋白c端酸性区域的单氨基酸取代对纤颤的影响很小。获得了20多种不同的单氨基酸取代，足以防止ot-synuclein的纤颤，其中大多数在成核和纤维伸长方面都受到损害。淀粉样蛋白纤颤调控序列决定因子的鉴定可能为设计肽类似物预防蛋白淀粉样变性提供有价值的信息。(c) 2008爱思唯尔公司版权所有。
alpha-Synuclein is a neural protein that comprises the fibrillar core of Lewy bodies, a histologically defining lesion of Parkinson's disease. To investigate the role of each specific residue of the alpha-synuclein molecule in fibril formation, amino acid substitutions were introduced throughout the molecule. Incorporation of proline, especially in the region spanning residues 37-89, drastically retarded fibril formation. Substitutions with polar residues showed that the hydrophobicity of the central hydrophobic region is also important in fibrillation regulation. In the N-terminal repeated region, increasing the number of negative charges interfered with fibrillation. In contrast, single amino acid substitutions in the C-terminal acidic region of alpha-synuclein had only minimal effects on fibrillation. More than 20 different single amino acid substitutions that were sufficient to prevent fibrillation of ot-synuclein were obtained, and most of them were impaired in both nucleation and fibril elongation. Identification of sequence determinants regulating fibrillation of amyloidogenic proteins may provide valuable information for designing peptide analog drugs to prevent protein amyloidosis. (c) 2008 Elsevier Inc. All rights reserved.