Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism
Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism
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DOI：
10.1074/jbc.m802376200
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发表时间：
2008-08-22
影响因子：
4.8
通讯作者：
Wu, Dianqing
中科院分区：
文献类型：
--
作者：
Wang, Ke;Zhang, Yazhou;Wu, Dianqing
WNT信号参与了广泛的发育、生理和病理生理过程，并受Dickkopf1(Dkk1)的负调控。Dkk1与两种跨膜蛋白结合，即低密度脂蛋白受体相关蛋白(LRP)5/6和Kreman。在这里，我们证明了Dkk1残基Arg(197)、Ser(198)和Lys(232)特异性地参与了它与Kreman的结合，而不是LRP6。这些残基定位在LRP6结合表面相反的表面上，该表面基于由Dkk2推导出的Dkk1的三维结构。我们惊讶地发现，携带Kreman关键结合残基Arg(197)、Ser(198)或Lys(232)突变的Dkk1突变体可以拮抗Wnt信号和野生型Dkk1。当LRP6和Kreman同时表达时，这些突变只会影响它们对抗Wnt信号的能力。这些结果表明，Kreman可能不是Dkk1介导的Wnt拮抗所必需的，只有当细胞表达高水平的LRP5/6时，Kreman才可能发挥作用。
Wnt signaling is involved in a wide range of developmental, physiological, and pathophysiological processes and is negatively regulated by Dickkopf1 (Dkk1). Dkk1 has been shown to bind to two transmembrane proteins, the low density lipoprotein receptor-related proteins (LRP) 5/6 and Kremen. Here, we show that Dkk1 residues Arg(197), Ser(198), and Lys(232) are specifically involved in its binding to Kremen rather than to LRP6. These residues are localized at a surface that is at the opposite side of the LRP6-binding surface based on a three-dimensional structure of Dkk1 deduced from that of Dkk2. We were surprised to find that the Dkk1 mutants carrying a mutation at Arg(197), Ser(198), or Lys(232), the key Kremen-binding residues, could antagonize Wnt signaling as well as the wild-type Dkk1. These mutations only affected their ability to antagonize Wnt signaling when both LRP6 and Kremen were coexpressed. These results suggest that Kremen may not be essential for Dkk1-mediated Wnt antagonism and that Kremen may only play a role when cells express a high level of LRP 5/6.