Structural and functional differences between 3-repeat and 4-repeat tau isoforms - Implications for normal tau function and the onset of neurodegenerative disease
Structural and functional differences between 3-repeat and 4-repeat tau isoforms - Implications for normal tau function and the onset of neurodegenerative disease
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DOI：
10.1074/jbc.m007489200
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发表时间：
2000-12-08
影响因子：
4.8
通讯作者：
Feinstein, SC
中科院分区：
文献类型：
--
作者：
Goode, BL;Chau, M;Feinstein, SC
Tau、MAP 2和MAP 4是微管相关蛋白（MAP）家族的成员，其各自表达为“3-重复”和“4-重复”同种型。这些同种型产生于严格控制的组织特异性和/或发育调节的31个氨基酸长的“inter-repeat：repeat模块”的选择性剪接，提高了不同MAP同种型可能具有一些不同功能能力的可能性。与这一假设一致，人类tau基因中的调节突变破坏了3-重复和4-重复tau亚型表达之间的正常平衡，导致了一系列被称为FTDP-17（与17号染色体相关的额颞叶痴呆和帕金森综合征）的神经退行性疾病，其特征在于病理性tau细丝的形成和神经元细胞死亡。不幸的是，关于异构体之间的结构和功能差异知之甚少。在我们之前的分析中，我们专注于4-重复tau的结构和功能。在这里，我们研究3-重复tau，产生一系列的截断，氨基酸取代，和内部缺失，并检查功能的后果。3-重复tau具有由其前两个重复序列和插入的重复序列间组成的“核心微管结合结构域”。这一观察结果与广泛持有的观点形成鲜明对比，该观点认为tau蛋白具有多个独立的微管蛋白结合位点，这些位点沿着蛋白质的长度顺序排列。此外，我们观察到，羧基末端序列下游的重复区域作出强有力的，但间接的贡献微管结合活性在5-重复tan，这是在相反的，这些相同的序列在4-重复tau的影响可以忽略不计。与以前的工作一起，这些数据表明，3-重复和4-重复tau假设复杂和不同的结构，差异调节，这反过来又表明，他们可能拥有亚型特异性的功能能力。异构体的具体结构和功能的相关性正常谭行动和神经退行性疾病的发病进行了讨论。
Tau, MAP2, and MAP4 are members of a microtubule-associated protein (MAP) family that are each expressed as "3-repeat" and "4-repeat" isoforms. These isoforms arise from tightly controlled tissue-specific and/or developmentally regulated alternative splicing of a 31-amino acid long "inter-repeat:repeat module," raising the possibility that different MAP isoforms may possess some distinct functional capabilities. Consistent with this hypothesis, regulatory mutations in the human tau gene that disrupt the normal balance between 3-repeat and 4-repeat tau isoform expression lead to a collection of neurodegenerative diseases known as FTDP-17 (fronto-temporal dementias and Parkinsonism Linked to chromosome 17), which are characterized by the formation of pathological tau filaments and neuronal cell death. Unfortunately, very little is known regarding structural and functional differences between the isoforms. In our previous analyses, we focused on 4-repeat tau structure and function. Here, we investigate 3-repeat tau, generating a series of truncations, amino acid substitutions, and internal deletions and examining the functional consequences. 3-Repeat tau possesses a "core microtubule binding domain" composed of its first two repeats and the intervening inter-repeat. This observation is in marked contrast to the widely held notion that tau possesses multiple independent tubulin-binding sites aligned in sequence along the length of the protein. In addition, we observed that the carboxyl-terminal sequences downstream of the repeat region make a strong but indirect contribution to microtubule binding activity in 5-repeat tan, which is in contrast to the negligible effect of these same sequences in 4-repeat tau. Taken together with previous work, these data suggest that 3-repeat and 4-repeat tau assume complex and distinct structures that are regulated differentially, which in turn suggests that they may possess isoform-specific functional capabilities. The relevance of isoform-specific structure and function to normal tan action and the onset of neurodegenerative disease are discussed.