Open AccessRecent studies of atomic‐resolution structures of tau protein and structure‐based inhibitors
Author(s) -
Zhu Lili,
Qian Zhenyu
Publication year - 2022
Publication title -
quantitative biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.707
H-Index - 15
eISSN - 2095-4697
pISSN - 2095-4689
DOI - 10.15302/j-qb-021-0271
Subject(s) - tau protein , tau pathology , senile plaques , neuroscience , protein aggregation , pathological , chemistry , amyloid (mycology) , amyloid β , tauopathy , hyperphosphorylation , drug target , disease , alzheimer's disease , computational biology , biology , medicine , neurodegeneration , biochemistry , pathology , phosphorylation
Background Alzheimer’s disease (AD) is one of the most popular tauopathies. Neurofibrillary tangles and senile plaques are widely recognized as the pathological hallmarks of AD, which are mainly composed of tau and β‐amyloid (Aβ) respectively. Recent failures of drugs targeting Aβ have led scientists to scrutinize the crucial impact of tau in neurodegenerative diseases. Mutated or abnormal phosphorylated tau protein loses affinity with microtubules and assembles into pathological accumulations. The aggregation process closely correlates to two amyloidogenic core of PHF6 ( 306 VQIVYK 311 ) and PHF6* ( 275 VQIINK 280 ) fragments. Moreover, tau accumulations display diverse morphological characteristics in different diseases, which increases the difficulty of providing a unifying neuropathological criterion for early diagnosis. Results This review mainly summarizes atomic‐resolution structures of tau protein in the monomeric, oligomeric and fibrillar states, as well as the promising inhibitors designed to prevent tau aggregation or disaggregate tau accumulations, recently revealed by experimental and computational studies. We also systematically sort tau functions, their relationship with tau structures and the potential pathological processes of tau protein. Conclusion The current progress on tau structures at atomic level of detail expands our understanding of tau aggregation and related pathology. We discuss the difficulties in determining the source of neurotoxicity and screening effective inhibitors. We hope this review will inspire new clues for designing medicines against tau aggregation and shed light on AD diagnosis and therapies.