Tankyrases are poly(ADP-ribose)polymerases (PARPs) which recognize their substrates via their ankyrin repeat cluster (ARC) domains. The human tankyrases (TNKS/TNKS2) contain five ARCs in their extensive N-terminal region; of these, four bind peptides present within tankyrase interactors and substrates. These short, linear segments, known as tankyrase-binding motifs (TBMs), contain some highly conserved features: an arginine at position 1, which occupies a predominantly acidic binding site, and a glycine at position 6 that is sandwiched between two aromatic side chains on the surface of the ARC domain. Tankyrases are involved in a multitude of biological functions, amongst them Wnt/β-catenin signaling, the maintenance of telomeres, glucose metabolism, spindle formation, the DNA damage response and Hippo signaling. As many of these are relevant to human disease, tankyrase is an important target candidate for drug development. With the emergence of non-catalytic (scaffolding) functions of tankyrase, it seems attractive to interfere with ARC function rather than the enzymatic activity of tankyrase. To study the mechanism of ARC-dependent recruitment of tankyrase binders and enable protein-observed NMR screening methods, we have as the first step obtained a full backbone and partial side chain assignment of TNKS2 ARC4. The assignment highlights some of the unusual structural features of the ARC domain.

中文翻译：

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人坦科聚合酶 2 的 ARC4 结构域的溶液 NMR 归属。


端锚聚合酶是聚（ADP-核糖）聚合酶（PARP），可通过锚蛋白重复簇（ARC）结构域识别其底物。人类端锚聚合酶 (TNKS/TNKS2) 在其广泛的 N 末端区域包含 5 个 ARC；其中，四种结合肽存在于端锚聚合酶相互作用物和底物中。这些短的线性片段，称为端锚聚合酶结合基序 (TBM)，包含一些高度保守的特征：位置 1 的精氨酸，主要占据酸性结合位点，位置 6 的甘氨酸，夹在两个芳香族侧链之间在ARC域的表面。端锚聚合酶参与多种生物功能，其中包括 Wnt/β-连环蛋白信号传导、端粒维持、葡萄糖代谢、纺锤体形成、DNA 损伤反应和 Hippo 信号传导。由于其中许多酶与人类疾病相关，坦聚合酶是药物开发的重要候选靶点。随着端锚聚合酶非催化（支架）功能的出现，干扰 ARC 功能而不是干扰端锚聚合酶的酶活性似乎更有吸引力。为了研究端锚聚合酶结合物的 ARC 依赖性招募机制并启用蛋白质观察的 NMR 筛选方法，我们第一步获得了 TNKS2 ARC4 的完整主链和部分侧链分配。该作业强调了 ARC 域的一些不寻常的结构特征。