Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.
Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.
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DOI：
10.1126/sciadv.add9789
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发表时间：
2023-02-03
期刊：
影响因子：
13.6
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中科院分区：
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阿尔茨海默病和相关的tau蛋白病的特征在于微管相关蛋白tau的致病性错误折叠和聚集。了解内源性分子伴侣如何调节tau蛋白错误折叠可以指导未来的治疗。在这里，我们表明，亲免素FKBP 12，12-kDa FK 506结合蛋白（也称为FKBP脯氨酰异构酶1A），通过陪伴单体tau蛋白中的特定结构来调节神经元的弹性。结合小鼠和细胞实验、体外聚集实验、单体tau的基于核磁共振的结构分析、位点特异性磷酸化和突变，以及使用基于神经网络的结构预测程序AlphaFold进行的基于结构的分析，我们定义了控制FKBP 12与tau结合的分子因素及其对tau诱导的神经毒性的影响。我们进一步证明了tau蛋白的酪氨酸磷酸化阻断了FKBP 12与tau蛋白中两个高度特异性结构基序的结合。我们的数据与先前的结果一起证明FKBP 12/tau在神经元和神经元缠结中的共定位支持FKBP 12在调节tau病理中的关键作用。分子研究揭示了亲免素FKBP 12在AD和其他tau蛋白病中神秘作用背后的机制。
Alzheimer’s disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance–based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network–based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology. Molecular studies shed light on the mechanisms behind the enigmatic role of immunophilin FKBP12 in AD and other tauopathies.
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