Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction
Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction
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DOI：
10.1101/2020.04.01.020057
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发表时间：
2020-04
期刊：
影响因子：
7.7
通讯作者：
Wei Kan;M. D. Enos;Elgin Korkmazhan;Stefan Muennich;Dong-Hua Chen;Melissa V. Gammons;Mansi Vasishtha;M. Bienz;A. Dunn;G. Skiniotis;W. Weis
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文献类型：
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作者：
Wei Kan;M. D. Enos;Elgin Korkmazhan;Stefan Muennich;Dong-Hua Chen;Melissa V. Gammons;Mansi Vasishtha;M. Bienz;A. Dunn;G. Skiniotis;W. Weis
在Wnt/β-连环蛋白信号转导中，转录共激活因子β-连环蛋白在包括支架蛋白Axin和相关激酶的复合体中受其磷酸化的调节。WNT与其辅助受体结合后，激活胞浆效应分子紊乱，导致轴突募集，抑制β-连环蛋白的磷酸化。这一过程需要DVL和Axin中存在的同源DIX结构域的相互作用，但在机械上是未定义的。我们发现DVL DIX在体外形成反平行的双链低聚物，而DVL在细胞内形成典型的内源表达水平的低聚物。Axin DIX(DAX)形成小的单链低聚物，但其自缔合性强于DIX。DAX封顶了DIX低聚体的末端，使得DIX低聚体最多有四个DAX结合位点。DIX-DAX相互作用的相对亲和力和化学计量比为有效抑制轴突重新募集到WNT受体复合体时β-连环蛋白的磷酸化提供了一种机制。
In Wnt/β-catenin signaling, the transcriptional coactivator β-catenin is regulated by its phosphorylation in a complex that includes the scaffold protein Axin and associated kinases. Wnt binding to its coreceptors activates the cytosolic effector Dishevelled (Dvl), leading to the recruitment of Axin and the inhibition of β-catenin phosphorylation. This process requires interaction of homologous DIX domains present in Dvl and Axin, but is mechanistically undefined. We show that Dvl DIX forms antiparallel, double-stranded oligomers in vitro, and that Dvl in cells forms oligomers typically <10 molecules at endogenous expression levels. Axin DIX (DAX) forms small single-stranded oligomers, but its self-association is stronger than that of DIX. DAX caps the ends of DIX oligomers, such that a DIX oligomer has at most four DAX binding sites. The relative affinities and stoichiometry of the DIX-DAX interaction provide a mechanism for efficient inhibition of β-catenin phosphorylation upon Axin recruitment to the Wnt receptor complex.