Xing Yi, Clements Wilson K, Le Trong Isolde, Hinds Thomas R, Stenkamp Ronald, Kimelman David, Xu Wenqing
Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
Mol Cell. 2004 Aug 27;15(4):523-33. doi: 10.1016/j.molcel.2004.08.001.
The tumor suppressor adenomatous polyposis coli (APC) plays a critical role in the turnover of cytosolic beta-catenin, the key effector of the canonical Wnt signaling pathway. APC contains seven 20 amino acid (20 aa) beta-catenin binding repeats that are required for beta-catenin turnover. We have determined the crystal structure of beta-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 beta-catenin and may thus compete for beta-catenin binding with all other beta-catenin armadillo repeat partners. Our biochemical studies show that phosphorylation of the APC 20 aa repeats increases the affinity of the repeats for beta-catenin by 300- to 500-fold and the phosphorylated 20 aa repeats prevent beta-catenin binding to Tcf. Our work suggests that the phosphorylation of the APC 20 aa repeats could be a critical switch for APC function.
肿瘤抑制因子腺瘤性结肠息肉病蛋白（APC）在胞质β-连环蛋白的周转中起关键作用，β-连环蛋白是经典Wnt信号通路的关键效应因子。APC含有七个20个氨基酸（20 aa）的β-连环蛋白结合重复序列，这些序列是β-连环蛋白周转所必需的。我们已经确定了与包含两个20 aa重复序列的磷酸化APC片段复合的β-连环蛋白的晶体结构。令人惊讶的是，一个单一的磷酸化20 aa重复序列及其侧翼区域覆盖了β-连环蛋白的整个结构凹槽，因此可能与所有其他β-连环蛋白犰狳重复序列伙伴竞争β-连环蛋白结合。我们的生化研究表明，APC 20 aa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300至500倍，并且磷酸化的20 aa重复序列阻止β-连环蛋白与Tcf结合。我们的工作表明，APC 20 aa重复序列的磷酸化可能是APC功能的关键开关。
