Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
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DOI：
10.1016/j.molcel.2016.06.019
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发表时间：
2016-08-04
期刊：
影响因子：
16
通讯作者：
Guettler S
中科院分区：
文献类型：
--
作者：
Mariotti L;Templeton CM;Ranes M;Paracuellos P;Cronin N;Beuron F;Morris E;Guettler S
聚（ADP-核糖）聚合酶（PARP）端锚聚合酶（TNKS和TNKS 2）对Wnt-β-连环蛋白信号传导至关重要，是Wnt依赖性癌症中有前途的治疗靶点。活性β-连环蛋白库通常受到破坏复合物的限制，其组装依赖于聚合物主支架蛋白AXIN。端锚聚合酶，聚（ADP-核糖基），从而使轴不稳定，也可以聚合，但这些聚合物的相关性仍然不清楚。我们报告的晶体结构的聚合TNKS和TNKS 2无菌α基序（SAM）域，揭示了多功能的头到尾的相互作用。由这些结构提供信息的生化研究表明，端锚聚合酶需要聚合来驱动β-连环蛋白依赖性转录。我们表明，聚合状态支持PARP活性，并允许端锚聚合酶通过亲合力依赖性轴蛋白结合有效地进入破坏复合物。这项研究为非膜封闭区室（信号体）中的调节信号转导提供了一个例子，并指出了抑制致癌Wnt信号传导中端锚聚合酶功能的新的潜在策略。SAM结构域晶体结构揭示了端锚聚合酶聚合的机制催化非依赖性端锚聚合酶支架驱动Wnt-β-catenin信号传导端锚聚合酶聚合支持PARP活性和轴蛋白结合端锚聚合酶的催化非依赖性支架支持Wnt-β-catenin信号传导。支架是介导的轴蛋白结合锚蛋白重复簇和聚合SAM域。在结构-功能方法中，Mariotti et al.显示聚合支持端锚聚合酶PARP活性，并使亲合力依赖性轴蛋白结合成为可能。
The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling. SAM domain crystal structures reveal mechanism of Tankyrase polymerization Catalysis-independent Tankyrase scaffolding drives Wnt-β-catenin signaling Tankyrase polymerization supports PARP activity and AXIN binding Catalysis-independent scaffolding by Tankyrase supports Wnt-β-catenin signaling. Scaffolding is mediated by AXIN-binding ankyrin repeat clusters and a polymerizing SAM domain. In a structure-function approach, Mariotti et al. show that polymerization supports Tankyrase PARP activity and enables avidity-dependent AXIN binding.