Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules
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DOI：
10.1083/jcb.201308068
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发表时间：
2013-12-23
影响因子：
7.8
通讯作者：
Spiliotis, Elias T.
中科院分区：
文献类型：
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作者：
Bai, Xiaobo;Bowen, Jonathan R.;Spiliotis, Elias T.
Septin 9(SEPT9)与微管相互作用，并在遗传性神经痛性肌营养不良(HNA)中发生突变，HNA是一种常染色体显性神经病。SEPT9与MTS相互作用的机制和海藻氨酸的分子基础尚不清楚。在这里，我们发现SEPT9的N-末端结构域包含新的重复基序K/R-x-x-E/D和R/K-R-x-E，它们通过与β-微管蛋白的酸性C-末端相互作用结合和结合MTS。丙氨酸扫描突变表明，K/R-R/x-x-E/D基序相互静电配对，以及β-微管蛋白的尾部，使Septin-Septin相互作用，将MT连接在一起。SEPT9亚型缺乏重复基序或含有HNA连锁突变R88W，该突变映射到R/K-R-x-E基序，减少细胞内MT捆绑，损害PC-12细胞中不对称突起的生长。因此，SEPT9重复基序结合并捆绑MT，从而促进不对称轴突的生长。这些结果首次揭示了Septin与MTS相互作用的机制以及HNA的分子和细胞基础。
Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel repeat motifs K/R-x-x-E/D and R/K-R-x-E, which bind and bundle MTs by interacting with the acidic C-terminal tails of beta-tubulin. Alanine scanning mutagenesis revealed that the K/R-R/x-x-E/D motifs pair electrostatically with one another and the tails of beta-tubulin, enabling septin-septin interactions that link MTs together. SEPT9 isoforms lacking repeat motifs or containing the HNA-linked mutation R88W, which maps to the R/K-R-x-E motif, diminished intracellular MT bundling and impaired asymmetric neurite growth in PC-12 cells. Thus, the SEPT9 repeat motifs bind and bundle MTs, and thereby promote asymmetric neurite growth. These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA.