Structural Insights into the Altering Function of CRMP2 by Phosphorylation.

IF 2 4区 生物学 Q4 CELL BIOLOGY
Takuya Sumi, Tsuyoshi Imasaki, Mari Aoki, Naoki Sakai, Eriko Nitta, Mikako Shirouzu, Ryo Nitta
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引用次数: 21

Abstract

Collapsin response mediator protein 2 (CRMP2) regulates neuronal polarity by controlling microtubule dynamics. CRMP2 activity is regulated by semaphorin-induced phosphorylation at the C-terminal tail domain. Unphosphorylated CRMP2 induces effective axonal microtubule formation to give the axonal characteristics to a neurite, whereas phosphorylated CRMP2 leads to the apparently opposite effect, growth cone collapse. We have recently characterized the structural detail of CRMP2-induced axonal microtubule formation (Niwa et al. (2017) Sci. Rep., 7: 10681). CRMP2 forms the hetero-trimer with GTP-tubulin to induce effective axonal microtubule formation in the future axon. Phosphorylation of CRMP2 has been reported to decrease the affinity between CRMP2 and the microtubule, albeit the molecular mechanisms of how the phosphorylation of CRMP2 changes the structure to achieve distinct effects from unphosphorylated CRMP2 is not well understood. Here we performed a series of biochemical and structural analyses of phospho-mimic CRMP2. Phosphorylation of CRMP2 undergoes small conformational changes at the C-terminal tail with shifting the surface charge, which not only alters the interactions within the CRMP2 tetramer but also alters the interactions with GTP-tubulin. Consequently, phospho-mimic CRMP2 fails to form a hetero-trimer with GTP-tubulin, thus losing the ability to establish and maintain the axonal microtubules.Key words: CRMP2, phosphorylation, microtubule, axon, crystal structure.

通过磷酸化改变CRMP2功能的结构见解。
坍缩反应介质蛋白2 (CRMP2)通过控制微管动力学调节神经元极性。CRMP2的活性受信号蛋白诱导的c端尾域磷酸化调控。未磷酸化的CRMP2诱导有效的轴突微管形成,赋予神经突轴突特征,而磷酸化的CRMP2导致明显相反的效果,生长锥塌陷。我们最近表征了crmp2诱导的轴突微管形成的结构细节(Niwa et al. (2017) Sci。众议员,7:10 681)。CRMP2与gtp -微管蛋白形成异源三聚体,诱导未来轴突有效的微管形成。据报道,CRMP2的磷酸化会降低CRMP2与微管之间的亲和力,尽管CRMP2的磷酸化如何改变结构以达到与未磷酸化CRMP2不同的效果的分子机制尚不清楚。我们对模拟磷酸的CRMP2进行了一系列生化和结构分析。CRMP2的磷酸化会在c端尾部发生微小的构象变化,改变表面电荷,这不仅改变了CRMP2四聚体内部的相互作用,也改变了与gtp -微管蛋白的相互作用。因此,磷酸化模拟CRMP2不能与gtp -微管蛋白形成异源三聚体,从而失去了建立和维持轴突微管的能力。关键词:CRMP2,磷酸化,微管,轴突,晶体结构
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来源期刊
Cell structure and function
Cell structure and function 生物-细胞生物学
CiteScore
2.50
自引率
0.00%
发文量
6
审稿时长
>12 weeks
期刊介绍: Cell Structure and Function is a fully peer-reviewed, fully Open Access journal. As the official English-language journal of the Japan Society for Cell Biology, it is published continuously online and biannually in print. Cell Structure and Function publishes important, original contributions in all areas of molecular and cell biology. The journal welcomes the submission of manuscripts on research areas such as the cell nucleus, chromosomes, and gene expression; the cytoskeleton and cell motility; cell adhesion and the extracellular matrix; cell growth, differentiation and death; signal transduction; the protein life cycle; membrane traffic; and organelles.
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