Goode B L, Chau M, Denis P E, Feinstein S C
Neuroscience Research Institute and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
J Biol Chem. 2000 Dec 8;275(49):38182-9. doi: 10.1074/jbc.M007489200.
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 3-repeat tau, 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 tau action and the onset of neurodegenerative disease are discussed.
Tau、MAP2和MAP4是微管相关蛋白（MAP）家族的成员，它们各自以“3重复”和“4重复”异构体形式表达。这些异构体源自对一个31个氨基酸长的“重复间：重复模块”进行严格控制的组织特异性和/或发育调控的可变剪接，这增加了不同MAP异构体可能具有一些独特功能的可能性。与这一假设一致，人类tau基因中的调节性突变破坏了3重复和4重复tau异构体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，其特征是病理性tau细丝的形成和神经元细胞死亡。不幸的是，关于这些异构体之间的结构和功能差异，人们知之甚少。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，生成了一系列截短、氨基酸替换和内部缺失，并研究了其功能后果。3重复tau具有一个由其前两个重复和中间的重复间区域组成的“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了显著对比，即tau沿着蛋白质长度序列排列有多个独立的微管蛋白结合位点。此外，我们观察到重复区域下游的羧基末端序列对3重复tau的微管结合活性有强烈但间接的贡献，这与这些相同序列在4重复tau中的可忽略不计的影响形成了对比。结合之前的工作，这些数据表明3重复和4重复tau呈现出复杂且不同的结构，这些结构受到不同的调控，这反过来表明它们可能具有异构体特异性的功能。讨论了异构体特异性结构和功能与正常tau作用及神经退行性疾病发病的相关性。
