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Progress in Chemistry 2022, Vol. 34 Issue (8): 1645-1660 DOI: 10.7536/PC211012 Previous Articles   Next Articles

• Review •

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: Revised: Online: Published:
  • 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)
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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
Fig. 1 Tau protein isoforms (A), phosphorylation modification sites (B) and other post-translational modification sites (C)
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
Scheme 1 Glycation of protein
Scheme 2 Acetylation of protein
Scheme 3 Polyaminations of protein
Scheme 4 Native chemical ligation and expressed protein ligation
Scheme 5 Synthesis of phosphorylated Tau4RD[18]
Scheme 6 Synthesis of ubiquitinated Tau4RD. (A) Synthesis of monoubiquitinated Tau4RD; (B) synthesis of diubiquitinated Tau4RD
Scheme 7 Synthesis of pS404 Tau[145]
Scheme 8 Synthesis of pY310 Tau and pS396 & pS404 Tau[21]
Scheme 9 Synthesis of AcK280 Tau[21]
Scheme 10 Synthesis of pS293 Tau and pS305 Tau[146]
Scheme 11 Synthesis of gS400 Tau[147]
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