The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
The Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
J Cell Biol. 2021 Apr 5;220(4). doi: 10.1083/jcb.202012112.
In Wnt/β-catenin signaling, the β-catenin protein level is deliberately controlled by the assembly of the multiprotein β-catenin destruction complex composed of Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), and others. Here we provide compelling evidence that formation of the destruction complex is driven by protein liquid-liquid phase separation (LLPS) of Axin. An intrinsically disordered region in Axin plays an important role in driving its LLPS. Phase-separated Axin provides a scaffold for recruiting GSK3β, CK1α, and β-catenin. APC also undergoes LLPS in vitro and enhances the size and dynamics of Axin phase droplets. The LLPS-driven assembly of the destruction complex facilitates β-catenin phosphorylation by GSK3β and is critical for the regulation of β-catenin protein stability and thus Wnt/β-catenin signaling.
在 Wnt/β-连环蛋白信号通路中，β-连环蛋白蛋白水平通过由 Axin、结肠腺瘤性息肉病基因（APC）、糖原合成酶激酶 3β（GSK3β）、酪蛋白激酶 1α（CK1α）和其他蛋白组成的多蛋白β-连环蛋白降解复合物的组装来进行精细调控。在这里，我们提供了令人信服的证据表明，降解复合物的形成是由 Axin 的蛋白质液-液相分离（LLPS）驱动的。Axin 中的一个无规则卷曲区域在驱动其 LLPS 中起着重要作用。相分离的 Axin 为招募 GSK3β、CK1α 和 β-连环蛋白提供了支架。APC 在体外也经历液-液相分离，并增强 Axin 相液滴的大小和动力学。降解复合物的 LLPS 驱动组装促进了 GSK3β 对 β-连环蛋白的磷酸化，这对于调节β-连环蛋白蛋白稳定性以及 Wnt/β-连环蛋白信号通路至关重要。
