Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains
Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains
复制标题
DOI：
10.1038/35083601
复制
发表时间：
2001-07-05
期刊：
影响因子：
64.8
通讯作者：
Leahy, DJ
中科院分区：
文献类型：
--
作者：
Dann, CE;Hsieh, JC;Leahy, DJ
七次跨膜蛋白卷曲家族的成员作为Wnt信号蛋白的受体（1）。Wnt蛋白在动物发育过程中不同组织的分化和模式化中具有重要作用（2，3），Wnt信号通路的不适当激活是许多癌症的关键特征（4）。Frizzled蛋白氨基末端的细胞外富含半胱氨酸结构域（CRD）与Wnt蛋白结合（1），可溶性蛋白中的同源结构域（称为分泌型Frizzled相关蛋白）也是如此（5）-其功能是Wnt信号传导的拮抗剂（6-8）。最近，一种LDL受体相关蛋白已被证明可作为Wnt蛋白的辅助受体，并以Wnt依赖性方式与Frizzled CRD结合（9-11）。为了研究Wnt信号传导复合物的分子性质，我们确定了来自小鼠卷曲蛋白8和分泌卷曲蛋白相关蛋白3的CRD的晶体结构。在这里，我们展示了一个以前未知的蛋白质折叠，以及识别Wnt结合位点的CRD突变的设计和解释。CRD表现出保守的二聚体界面，这可能是Wnt信号传导的一个特征。这项工作为研究蛋白质中的同源CRD提供了一个框架，包括肌肉特异性激酶和Smoothened，Hedgehog信号传导途径的一个组成部分（12，13）。
Members of the Frizzled family of seven-pass transmembrane proteins serve as receptors for Wnt signalling proteins(1). Wnt proteins have important roles in the differentiation and patterning of diverse tissues during animal development(2,3), and inappropriate activation of Wnt signalling pathways is a key feature of many cancers(4). An extracellular cysteine-rich domain (CRD) at the amino terminus of Frizzled proteins binds Wnt proteins(1), as do homologous domains in soluble proteins-termed secreted Frizzled-related proteins(5) - that function as antagonists of Wnt signalling(6-8). Recently, an LDL-receptor-related protein has been shown to function as a co-receptor for Wnt proteins and to bind to a Frizzled CRD in a Wnt-dependent manner(9-11). To investigate the molecular nature of the Wnt signalling complex, we determined the crystal structures of the CRDs from mouse Frizzled 8 and secreted Frizzled-related protein 3. Here we show a previously unknown protein fold, and the design and interpretation of CRD mutations that identify a Wnt-binding site. CRDs exhibit a conserved dimer interface that may be a feature of Wnt signalling. This work provides a framework for studies of homologous CRDs in proteins including muscle-specific kinase and Smoothened, a component of the Hedgehog signalling pathway(12,13).