Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.
Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.
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DOI：
10.1016/j.molcel.2004.08.001
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发表时间：
2004-08
期刊：
影响因子：
16
通讯作者：
Y. Xing;W. Clements;I. Le Trong;T. Hinds;R. Stenkamp;D. Kimelman;Wenqing Xu
中科院分区：
文献类型：
--
作者：
Y. Xing;W. Clements;I. Le Trong;T. Hinds;R. Stenkamp;D. Kimelman;Wenqing Xu
肿瘤抑制因子结肠腺瘤性息肉病在细胞内β-连环蛋白的周转过程中起着关键作用，它是典型的Wnt信号通路的关键效应因子。APC包含7个20个氨基酸(20aa)的β-连环蛋白结合重复序列，这是β-连环蛋白转换所必需的。我们测定了β-连环蛋白与一个含有两个20个氨基酸重复序列的磷酸化APC片段形成的络合物的晶体结构。令人惊讶的是，一个磷酸化的20个氨基酸重复序列及其侧翼区域覆盖了β-连环蛋白的整个结构沟，因此可能与所有其他β-连环蛋白重复序列伙伴竞争β-连环蛋白结合。我们的生化研究表明，APC20个氨基酸重复序列的磷酸化使重复序列与β-连环蛋白的亲和力增加了300-500倍，并且磷酸化的20个氨基酸重复序列阻止了β-连环蛋白与Tcf的结合。我们的工作表明，APC 20AA重复序列的磷酸化可能是APC功能的关键开关。
The tumor suppressor adenomatous polyposis coli (APC) plays a critical role in the turnover of cytosolic β-catenin, the key effector of the canonical Wnt signaling pathway. APC contains seven 20 amino acid (20 aa) β-catenin binding repeats that are required for β-catenin turnover. We have determined the crystal structure of β-catenin in complex with a phosphorylated APC fragment containing two 20 aa repeats. Surprisingly, one single phosphorylated 20 aa repeat, together with its flanking regions, covers the entire structural groove of β-catenin and may thus compete for β-catenin binding with all other β-catenin armadillo repeat partners. Our biochemical studies show that phosphorylation of the APC 20 aa repeats increases the affinity of the repeats for β-catenin by 300- to 500-fold and the phosphorylated 20 aa repeats prevent β-catenin binding to Tcf. Our work suggests that the phosphorylation of the APC 20 aa repeats could be a critical switch for APC function.