Mechanism of phosphorylation-dependent binding of APC to β-catenin and its role in β-catenin degradation
Mechanism of phosphorylation-dependent binding of APC to β-catenin and its role in β-catenin degradation
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DOI：
10.1016/j.molcel.2004.08.010
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发表时间：
2004-08-27
期刊：
影响因子：
16
通讯作者：
Weis, WI
中科院分区：
文献类型：
--
作者：
Ha, NC;Tonozuka, T;Weis, WI
转录辅激活因子β-连环蛋白介导Writ生长因子信号传导。在缺乏Writ信号的情况下，酪蛋白激酶1（CK 1）和糖原合成酶激酶-3 β（GSK-3 β）磷酸化胞质β-连环蛋白，从而标记它以被泛素/蛋白体机制识别和破坏。磷酸化发生在多蛋白复合物中，包括激酶、β-连环蛋白、轴蛋白和腺瘤性结肠息肉病（APC）蛋白。APC在这一过程中的作用知之甚少。CK 1 β和GSK-3 β磷酸化APC，这增加了其对β-连环蛋白的亲和力。结合β-连环蛋白的磷酸化和非磷酸化APC的晶体结构揭示了CK 1和GSK-3 β底物序列相互引发产生的磷酸化依赖性结合基序。Axin被证明是这些激酶磷酸化底物的支架。磷酸化APC和轴蛋白结合到β-连环蛋白的相同表面，并直接竞争β-连环蛋白。结构和生化数据表明，一个新的模型APC如何在β-连环蛋白降解的功能。
The transcriptional coactivator beta-catenin mediates Writ growth factor signaling. In the absence of a Writ signal, casein kinase 1 (CK1) and glycogen synthase kinase-3beta (GSK-3beta) phosphorylate cytosolic beta-catenin, thereby flagging it for recognition and destruction by the ubiquitin/proteosome machinery. Phosphorylation occurs in a multiprotein complex that includes the kinases, beta-catenin, axin, and the Adenomatous Polyposis Coli (APC) protein. The role of APC in this process is poorly understood. CK1epsilon and GSK-3beta phosphorylate APC, which increases its affinity for beta-catenin. Crystal structures of phosphorylated and nonphosphoryated APC bound to beta-catenin reveal a phosphorylation-dependent binding motif generated by mutual priming of CK1 and GSK-3beta substrate sequences. Axin is shown to act as a scaffold for substrate phosphorylation by these kinases. Phosphorylated APC and axin bind to the same surface of, and compete directly for, beta-catenin. The structural and biochemical data suggest a novel model for how APC functions in beta-catenin degradation.