Noncore Residues Influence the Kinetics of Functional TTR105-115-Based Amyloid Fibril Assembly
Noncore Residues Influence the Kinetics of Functional TTR105-115-Based Amyloid Fibril Assembly
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DOI：
10.1016/j.jmb.2011.12.020
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发表时间：
2012-08-10
影响因子：
5.6
通讯作者：
Gras, Sally L.
中科院分区：
文献类型：
--
作者：
Bongiovanni, Marie N.;Puri, Dhivya;Gras, Sally L.
已知形成淀粉样原纤维核心结构的多肽序列中的突变会影响原纤维组装和稳定性，但变化对非核心残基的影响，特别是与保留原纤维核心的功能化原纤维有关，尚未得到系统研究。在本研究中，短肽序列TTR105-115（也称为TTR1）和功能化变体TTR1-RGD和TTR1-RAD被用作模型系统来研究非核心残基对原纤维组装动力学的影响。 TTR1-RGD 和 TTR1-RAD 中的非核心残基影响非种子样品中原纤维组装的速率，与丙氨酸相比，位置 15 的甘氨酸残基增加了聚集速率。还发现成熟的 TTR1-RGD 原纤维更容易断裂，表明机械性能可能存在差异。每种类型原纤维的片段都能够自播种和交叉播种，产生具有高度相似的交叉p核心结构的原纤维。自播种样品观察到的相似组装速率反映了为这些肽计算的相似的伸长自由能，而交叉播种原纤维的形态由单体肽的性质及其在原丝和原纤维内的大分子排列决定。这些发现说明非核心残基对原纤维形成和原纤维特性的影响，并证明在设计用于生产自组装功能原纤维材料的序列时应考虑非核心残基的影响。 (C) 2011 Elsevier Ltd. 保留所有权利。
Mutations in the polypeptide sequence that forms the core structure of amyloid fibrils are known to impact on fibril assembly and stability but the effect of changes on noncore residues, particularly relating to functionalized fibrils where the fibril core is preserved, has not been systematically examined. In this study, the short peptide sequence TTR105-115 (also known as TTR1) and the functionalized variants TTR1-RGD and TTR1-RAD are used as a model system to investigate the effect of noncore residues on the kinetics of fibril assembly. The noncore residues in TTR1-RGD and TTR1-RAD influence the rate of fibril assembly in non-seeded samples with the glycine residue at position 15 increasing the rate of aggregation compared to alanine. Mature TTR1-RGD fibrils were also found to fragment more readily, indicating possible differences in mechanical properties. Fragments of each type of fibril are capable of self- and cross-seeding, generating fibrils with a highly similar cross-p core structure. The similar rates of assembly observed for self-seeded samples reflect the similar free energy of elongation calculated for these peptides, while the morphology of cross-seeded fibrils is determined by the properties of the monomeric peptide and its macromolecular arrangement within the protofilaments and fibrils. These findings illustrate that noncore residues impact on fibril formation and fibril properties and demonstrate that the influence of noncore residues should be considered when designing sequences for the production of self-assembling functional fibrillar materials. (C) 2011 Elsevier Ltd. All rights reserved.