Ha Nam-Chul, Tonozuka Takashi, Stamos Jennifer L, Choi Hee-Jung, Weis William I
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94043, USA.
Mol Cell. 2004 Aug 27;15(4):511-21. doi: 10.1016/j.molcel.2004.08.010.
The transcriptional coactivator beta-catenin mediates Wnt growth factor signaling. In the absence of a Wnt 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 nonphosphorylated 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.
转录共激活因子β-连环蛋白介导Wnt生长因子信号传导。在没有Wnt信号的情况下，酪蛋白激酶1（CK1）和糖原合酶激酶-3β（GSK-3β）使胞质β-连环蛋白磷酸化，从而标记它以便被泛素/蛋白酶体机制识别和破坏。磷酸化发生在一个多蛋白复合物中，该复合物包括激酶、β-连环蛋白、轴蛋白和腺瘤性息肉病大肠杆菌（APC）蛋白。APC在这个过程中的作用尚不清楚。CK1ε和GSK-3β使APC磷酸化，这增加了它对β-连环蛋白的亲和力。与β-连环蛋白结合的磷酸化和非磷酸化APC的晶体结构揭示了由CK1和GSK-3β底物序列相互引发产生的磷酸化依赖性结合基序。轴蛋白被证明作为这些激酶进行底物磷酸化的支架。磷酸化的APC和轴蛋白结合到β-连环蛋白的同一表面，并直接竞争β-连环蛋白。结构和生化数据为APC在β-连环蛋白降解中发挥作用提出了一个新模型。
