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化学进展 2022, Vol. 34 Issue (8): 1645-1660 DOI: 10.7536/PC211012 前一篇   后一篇

• 综述 •

翻译后修饰Tau蛋白及其化学全/半合成

林业竣1, 李艳梅1,2,3,*()   

  1. 1 清华大学化学系 生命有机磷化学及化学生物学教育部重点实验室 北京 100084
    2 北京脑重大疾病研究院 北京 100069
    3 清华大学合成与系统生物学研究中心 北京 100084
  • 收稿日期:2021-10-19 修回日期:2021-12-20 出版日期:2022-04-01 发布日期:2022-04-01
  • 通讯作者: 李艳梅
  • 基金资助:
    国家重点研发计划(2018YFA0507600); 国家重点研发计划(2019YFA0904200); 国家自然科学基金项目(92053108)
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Chemical Synthesis/Semisynthesis of Post-Translational Modified Tau Protein

Yehjun Lim1, Yanmei Li1,2,3()   

  1. 1 Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University,Beijing 100084, China
    2 Beijing Institute for Brain Disorders, Capital Medical University,Beijing 100069, China
    3 Center for Synthetic and System Biology, Tsinghua University,Beijing 100084, China
  • Received:2021-10-19 Revised:2021-12-20 Online:2022-04-01 Published:2022-04-01
  • Contact: Yanmei Li
  • Supported by:
    National Key Research and Development Program of China(2018YFA0507600); National Key Research and Development Program of China(2019YFA0904200); National Natural Science Foundation of China(92053108)

Tau蛋白是一种微管相关蛋白,有6种亚型,由352~441氨基酸组成。Tau蛋白的错误折叠和聚集与Tau蛋白病(Tauopathies),如阿尔茨海默病(AD)密切相关。目前在临床患者样本中可检测到具有各种翻译后修饰的Tau蛋白,这些翻译后修饰可能是AD发病机制的关键因素。本文综述了Tau蛋白常见的翻译后修饰,尤其是退行性疾病相关的翻译后修饰,以及化学全/半合成制备具有特定位点修饰、均一的Tau蛋白的进展。通过回顾翻译后修饰Tau蛋白的研究,可以更深入理解翻译后修饰对Tau蛋白的生理和病理作用,阐明翻译后修饰的调控机制,为相关疾病诊疗研究打下基础。

关键词： Tau蛋白, Tau蛋白病, 翻译后修饰, 蛋白合成, 蛋白半合成

Tau protein is a microtubule-associated protein that contains six isoforms and consists 352~441 amino acids. Misfolding and aggregation of Tau protein are closely related to Tauopathies, including Alzheimer’s disease (AD). In the brain of AD patients, it is indicated that post-translational modification plays a key factor in the pathogenesis of AD. This paper reviews the post-translational modifications of Tau protein and the progress in chemical synthetic/semisynthetic preparation of uniform Tau protein with specific site modification. Reviewing the research of post-translational modification of Tau protein, clarifies the regulatory mechanism of post-translational modification, which will help us to understand the physiological and pathological effects of post-translational modification on Tau protein and further develop potential disease treatment methods.

Contents

1 Introduction

2 The structure and function of Tau protein

3 Post-translational modification of Tau protein

3.1 Phosphorylation

3.2 Glycosylation and glycation

3.3 Acetylation

3.4 Ubiquitination

3.5 Nitration

3.6 Other post-translational modifications

4 Preparation of post-translationally modified Tau protein by chemical synthetic/semisynthetic

4.1 Preparation of post-translationally modified Tau protein microtubule binding domain by chemical synthesis

4.2 Preparation of post-translationally modified full length Tau protein by chemical synthetic/semisynthetic

5 Conclusion and outlook

Key words: Tau protein, Tauopathies, post-translational modification, protein synthesis, protein semisynthetic
()
图1 Tau蛋白的各种亚型(A)、磷酸化修饰位点(B)和其他翻译后修饰位点(C)
Fig. 1 Tau protein isoforms (A), phosphorylation modification sites (B) and other post-translational modification sites (C)
表1 磷酸激酶及其磷酸化Tau蛋白的位点
Table 1 The site of Tau protein that can be phosphorylated by phosphokinase
Kinase Phosphorylation sites ref
GSK-3 T69, T153, T175, T181, S184, Ser191, S198, S199, S202, T205, S210, T212, S214, T217, T231, S235, S237, S258, S262, S289, Ser324, S356, S396, S400, T403, S404, S409, S412, S413, T414, S416 39,45⇓⇓⇓⇓⇓~51
CDK5 T181, S199, S202, T205, T212, S214, T217, T231, S235, S396, S404 42,52⇓~54
JNK T175, T181,S199, S202, T205, T212, Ser214, T217, T231, S235, S237, S238, S356, S396, S404, S422 45,55,56
CK1 S113, S184, Ser185, S198, S202, T205, S208, S210, T212, S214, S237, S238, S258, S262, S289, S356, S396, S404, S412, S413, T414, S416, S433, S435 46
PKA S198, S199, S202, S210, T212, S214, T217, T231, S235, S258, S262, Ser324, S356, S409, S412, S413, T414, S416, S422, S435 57⇓⇓~60
DYRK T181, S199, S202, T205, T212, T217, T231, S396, S400, S404, S422 61⇓~63
MARK S262, S293, S324, S356 64,65
AMPK T71, T169, S195, S208, S214, T231, S235, S241, T245, S258, S262, S289, S293, S305, S324, S352, S356, T373, T377, T386, S396, S400, T403 66,67
Fyn Y18, Y197 68
Lck Y18, Y197, Y310, Y394 68
c-Abl Y197, Y310, Y394 69
图式1 蛋白糖化反应
Scheme 1 Glycation of protein
图式2 蛋白乙酰化反应
Scheme 2 Acetylation of protein
图式3 蛋白聚胺化反应
Scheme 3 Polyaminations of protein
图式4 自然化学连接法和表达蛋白连接法
Scheme 4 Native chemical ligation and expressed protein ligation
图式5 磷酸化Tau4RD的合成[18]
Scheme 5 Synthesis of phosphorylated Tau4RD[18]
图式6 泛素化Tau4RD的合成。(A)单泛素化Tau4RD的合成;(B)双泛素化Tau4RD的合成
Scheme 6 Synthesis of ubiquitinated Tau4RD. (A) Synthesis of monoubiquitinated Tau4RD; (B) synthesis of diubiquitinated Tau4RD
图式7 pS404 Tau的合成[145]
Scheme 7 Synthesis of pS404 Tau[145]
图式8 pY310 Tau和pS396 & pS404 Tau的合成[21]
Scheme 8 Synthesis of pY310 Tau and pS396 & pS404 Tau[21]
图式9 AcK280 Tau的合成[21]
Scheme 9 Synthesis of AcK280 Tau[21]
图式10 pS293 Tau和pS305 Tau的合成[146]
Scheme 10 Synthesis of pS293 Tau and pS305 Tau[146]
图式11 gS400 Tau的合成[147]
Scheme 11 Synthesis of gS400 Tau[147]
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