Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling
Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling
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DOI：
10.1016/j.str.2016.06.022
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发表时间：
2016-09-06
期刊：
影响因子：
5.7
通讯作者：
Pascal, John M.
中科院分区：
文献类型：
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作者：
Riccio, Amanda A.;McCauley, Michael;Pascal, John M.
tankyase -1 （TNKS1/PARP-5a）是一种多聚（adp -核糖）聚合酶（PARP）酶，可调节多种细胞过程，产生多聚（adp -核糖）翻译后修饰，从而导致靶蛋白转换。因此，TNKS1控制信号通路关键组分的蛋白水平，包括Axin1，它是典型Wnt信号中破坏复合物的限制性组分，可降解β -连环蛋白以阻止其在基因表达中的共激活因子功能。对细胞信号通路中TNKS1调控的分子水平认识有限。TNKS1具有一个已知介导聚合的无菌α基序（SAM）结构域，但SAM聚合的功能要求尚未得到评估。我们已经确定了野生型人类TNKS1 SAM结构域的晶体结构，并使用基于结构的诱变来破坏聚合物的形成，并评估了TNKS1调节β -连环蛋白依赖转录的后果。我们的数据表明，SAM聚合物对TNKS1的催化活性至关重要，并允许TNKS1有效地进入细胞质信号复合物。
Tankyrase-1 (TNKS1/PARP-5a) is a poly(ADP-ribose) polymerase (PARP) enzyme that regulates multiple cellular processes creating a poly(ADP-ribose) post-translational modification that can lead to target protein turnover. TNKS1 thereby controls protein levels of key components of signaling pathways, including Axin1, the limiting component of the destruction complex in canonical Wnt signaling that degrades beta-catenin to prevent its coactivator function in gene expression. There are limited molecular level insights into TNKS1 regulation in cell signaling pathways. TNKS1 has a sterile alpha motif (SAM) domain that is known to mediate polymerization, but the functional requirement for SAM polymerization has not been assessed. We have determined the crystal structure of wild-type human TNKS1 SAM domain and used structure-based mutagenesis to disrupt polymer formation and assess the consequences on TNKS1 regulation of beta-catenin-dependent transcription. Our data indicate the SAM polymer is critical for TNKS1 catalytic activity and allows TNKS1 to efficiently access cytoplasmic signaling complexes.