Identification of a novel site of interaction between ataxin-3 and the amyloid aggregation inhibitor polyglutamine binding peptide 1.
Identification of a novel site of interaction between ataxin-3 and the amyloid aggregation inhibitor polyglutamine binding peptide 1.
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DOI：
10.1177/1469066717729298
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Ashcroft AE
中科院分区：
文献类型：
--
作者：
Knight PD;Karamanos TK;Radford SE;Ashcroft AE
淀粉样蛋白疾病代表了发达国家日益增长的社会和经济负担。了解组装途径和抑制淀粉样蛋白形成是开发治疗这些疾病的疗法的关键。神经退行性疾病Machado-Joseph病的特征在于蛋白质ataxin-3的自我聚集。Ataxin-3由一个球状的N-末端Josephin结构域和一个非结构化的、动态无序的C-末端结构域组成，其中N-末端Josephin结构域可以聚集成曲线状的原纤维，C-末端结构域包含三个由多聚谷氨酰胺延伸分开的泛素相互作用基序。当多聚谷氨酰胺区域扩展到50个残基以上时，共济失调蛋白-3经历第二阶段的聚集，其中形成长而直的淀粉样纤维。聚谷氨酰胺聚集的肽抑制剂，称为polyQ结合肽1，先前已显示可防止共济失调蛋白-3原纤维的成熟。然而，这种抑制的机制仍不清楚。使用纳米电喷雾电离质谱，我们证明polyQ结合肽1结合单体共济失调蛋白-3。通过研究polyQ结合肽1结合缺乏一个或多个结构域的截短型共济失调蛋白-3构建体的能力，我们将这种相互作用的位点定位于紧邻Josephin结构域C末端的39个残基序列。结果表明，polyQ结合肽1抑制多聚谷氨酰胺聚集的新机制，其中结合到多聚谷氨酰胺道外的区域可以防止原纤维形成，突出了多聚谷氨酰胺侧翼区域在控制聚集和疾病中的重要性。
Amyloid diseases represent a growing social and economic burden in the developed world. Understanding the assembly pathway and the inhibition of amyloid formation is key to developing therapies to treat these diseases. The neurodegenerative condition Machado–Joseph disease is characterised by the self-aggregation of the protein ataxin-3. Ataxin-3 consists of a globular N-terminal Josephin domain, which can aggregate into curvilinear protofibrils, and an unstructured, dynamically disordered C-terminal domain containing three ubiquitin interacting motifs separated by a polyglutamine stretch. Upon expansion of the polyglutamine region above 50 residues, ataxin-3 undergoes a second stage of aggregation in which long, straight amyloid fibrils form. A peptide inhibitor of polyglutamine aggregation, known as polyQ binding peptide 1, has been shown previously to prevent the maturation of ataxin-3 fibrils. However, the mechanism of this inhibition remains unclear. Using nanoelectrospray ionisation-mass spectrometry, we demonstrate that polyQ binding peptide 1 binds to monomeric ataxin-3. By investigating the ability of polyQ binding peptide 1 to bind to truncated ataxin-3 constructs lacking one or more domains, we localise the site of this interaction to a 39-residue sequence immediately C-terminal to the Josephin domain. The results suggest a new mechanism for the inhibition of polyglutamine aggregation by polyQ binding peptide 1 in which binding to a region outside of the polyglutamine tract can prevent fibril formation, highlighting the importance of polyglutamine flanking regions in controlling aggregation and disease.
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影响因子：
3.4
作者：
Darnell, Gregory D.;Derryberry, JohnMark;Meredith, Stephen C.
通讯作者：
Meredith, Stephen C.
DOI：
10.1073/pnas.0502068102
发表时间：
2005-09-20
影响因子：
11.1
作者：
Armen, RS;Bernard, BM;Daggett, V
通讯作者：
Daggett, V
影响因子：
30.8
作者：
KAWAGUCHI, Y;OKAMOTO, T;KAKIZUKA, A
通讯作者：
KAKIZUKA, A
影响因子：
4.8
作者：
Nagai, Y;Tucker, T;Burke, JR
通讯作者：
Burke, JR
影响因子：
3.9
作者：
Apicella, Alessandra;Natalello, Antonino;Regonesi, Maria Elena
通讯作者：
Regonesi, Maria Elena