The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation
The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation
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DOI：
10.1002/1873-3468.13218
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发表时间：
2018-09-01
期刊：
影响因子：
3.5
通讯作者：
Ito, Nobutoshi
中科院分区：
文献类型：
--
作者：
Ikura, Teikichi;Tochio, Naoya;Ito, Nobutoshi
老年痴呆症疾病相关蛋白Tau被过度磷酸化并聚集成神经元缠结（NFT）。磷酸化Thr 231-Pro232的顺式异构体已被提出作为聚集（Tistauosis）的前体，但这种聚集方案尚未被完全接受。在这里，我们合成了包含磷酸化区域（包括Thr 231-Pro232）和聚集核心区域R1的肽，以研究Tau的异构体特异性聚集。磷酸化的肽形成淀粉样聚集体。甚至在肽基-脯氨酰-异构酶Pin 1的催化结构域的存在下也观察到这种聚集，所述肽基-脯氨酰-异构酶Pin 1优先将顺式异构体转化为反式异构体，但在Pin 1的WW结构域选择性结合到反式异构体的存在下急剧降低。这些结果表明，反式异构体是聚集倾向和WW结构域的Pin 1有效地抑制其聚集。
In Alzheimer's. the disease-related protein Tau is hyperphosphorylated and aggregates into neurofibrillary tangles (NFT). The cis isomer of the phosphorylated Thr231-Pro232 has been proposed as a precursor of aggregation (Tistauosis), but this aggregation scheme is not yet completely accepted. Here, we synthesized peptides comprising a phosphorylated region including Thr231-Pro232 and an aggregation-core region R1 to investigate isomer-specific-aggregation of Tau. The phosphorylated peptide formed amyloid-like aggregation. This aggregation was observed even in the presence of the catalytic domain of the peptidyl-prolyl-isomerase Pin1, which preferentially converts the cis isomer to the trans isomer, but decreased drastically in the presence of the WW domain of Pin1 selectively binding to the trans isomer. These results indicate that the trans isomer is aggregation-prone and that the WW domain of Pin1 effectively inhibits its aggregation.