Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity.
Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity.
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DOI：
10.3390/molecules25235698
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发表时间：
2020-12-03
期刊：
影响因子：
--
通讯作者：
Brito RMM
中科院分区：
文献类型：
--
作者：
Frangolho A;Correia BE;Vaz DC;Almeida ZL;Brito RMM
淀粉样变性的分子特征之一是有序的蛋白质聚集，包括最初形成的可溶性蛋白质低聚体，最终生长成不溶的纤维。对淀粉样蛋白纤维形成和疾病发展至关重要的分子物种的鉴定和表征一直是文献中密集分析的焦点。在这里，我们使用光诱导未修饰蛋白的交联物(PICUP)，研究了人类转甲状腺蛋白(TTR)的早期寡聚阶段，TTR是一种与淀粉样病(ATTR淀粉样变性)相关的血浆蛋白，具有多种临床表现。通过比较，野生型TTR(TTRUT)和几个TTR变异体(TTRV30M、TTRL55P和TTRT119M)的齐聚过程明显显示出与淀粉样变异体不同的齐聚动力学，但齐聚机理相似。分析中的TTR淀粉样变异体的齐聚动力学与其淀粉样变异体的潜能有很好的相关性，大多数淀粉样变异体聚集得更快(TTRL55P>；TTRV30M>；TTRUPT)。此外，这些变体的早期齐聚机理包括逐步将单体单元添加到不断增长的低聚物中。观察到非淀粉样变性TTRT119M变体的行为完全不同，它在相同的酸性条件下不会形成低聚物，甚至在更长的孵育时间内也不会形成寡聚体。彻底表征TTR寡聚的初始步骤对于更好地了解ATTR细胞毒性的来源以及开发治疗ATTR淀粉样变性的新的治疗策略至关重要。
One of the molecular hallmarks of amyloidoses is ordered protein aggregation involving the initial formation of soluble protein oligomers that eventually grow into insoluble fibrils. The identification and characterization of molecular species critical for amyloid fibril formation and disease development have been the focus of intense analysis in the literature. Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases (ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M) clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants under analysis showed a good correlation with their amyloidogenic potential, with the most amyloidogenic variants aggregating faster (TTRL55P > TTRV30M > TTRwt). Moreover, the early stage oligomerization mechanism for these variants involves stepwise addition of monomeric units to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for the treatment of ATTR amyloidosis.
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影响因子：
3.7
作者：
Coelho T;Merlini G;Bulawa CE;Fleming JA;Judge DP;Kelly JW;Maurer MS;Planté-Bordeneuve V;Labaudinière R;Mundayat R;Riley S;Lombardo I;Huertas P
通讯作者：
Huertas P
影响因子：
4.8
作者：
Ho, Lap;Ferruzzi, Mario G.;Pasinetti, Giulio Maria
通讯作者：
Pasinetti, Giulio Maria
影响因子：
16
作者：
Eneqvist, T;Andersson, K;Sauer-Eriksson, AE
通讯作者：
Sauer-Eriksson, AE
DOI：
10.1073/pnas.96.11.6020
发表时间：
1999-05-25
影响因子：
11.1
作者：
Fancy, DA;Kodadek, T
通讯作者：
Kodadek, T
DOI：
10.2174/1568013033483230
发表时间：
2003-12-01
期刊：
Current Medicinal Chemistry - Immunology Endocrine & Metabolic Agents
影响因子：
--
作者：
Brito, Rui M. M.;Damas, Ana Margarida;Joao-Saraiva, Maria
通讯作者：
Joao-Saraiva, Maria