Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of frizzled
Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of frizzled
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DOI：
10.1016/s1097-2765(03)00427-1
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发表时间：
2003-11-01
期刊：
影响因子：
16
通讯作者：
Zheng, J
中科院分区：
文献类型：
--
作者：
Wong, HC;Bourdelas, A;Zheng, J
细胞质蛋白Dishevelled（Dvl）和相关的膜结合受体Frizzled（Fz）在经典和非经典Wnt信号通路中是必不可少的。然而，这种信号转导的分子机制还没有很好地理解。通过使用NMR光谱，我们确定Fz的内部序列与Dvl的PDZ结构域中的常规肽结合位点结合;这种类型的位点通常与C-末端结合基序结合。Dvl抑制剂Dapper（Dpr）的C-末端区域与Frodo结合至相同位点。在非洲爪蟾中，Dvl结合肽Fz和Dpr/Frodo以剂量依赖性方式抑制经典Wnt信号传导并阻断Wnt诱导的次级轴形成，但不阻断DEP结构域介导的非经典Wnt信号传导。总之，我们的结果确定了Wnt途径中缺失的分子连接。Dvl PDZ结构域及其结合配偶体的结合亲和力的差异在调节Dvl的信号转导中可能是重要的。
The cytoplasmic protein Dishevelled (Dvl) and the associated membrane-bound receptor Frizzled (Fz) are essential in canonical and noncanonical Wnt signaling pathways. However, the molecular mechanisms underlying this signaling are not well understood. By using NMR spectroscopy, we determined that an internal sequence of Fz binds to the conventional peptide binding site in the PDZ domain of Dvl; this type of site typically binds to C-terminal binding motifs. The C-terminal region of the Dvl inhibitor Dapper (Dpr) and Frodo bound to the same site. In Xenopus, Dvl binding peptides of Fz and Dpr/Frodo inhibited canonical Wnt signaling and blocked Wnt-induced secondary axis formation in a dose-dependent manner, but did not block noncanonical Wnt signaling mediated by the DEP domain. Together, our results identify a missing molecular connection within the Wnt pathway. Differences in the binding affinity of the Dvl PDZ domain and its binding partners may be important in regulating signal transduction by Dvl.