Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).
Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).
复制标题
DOI：
10.1021/acschembio.1c00693
复制
发表时间：
2021-12-17
影响因子：
4
通讯作者：
Crews, Craig M.
中科院分区：
文献类型：
--
作者：
Chen, Po-Han;Hu, Zhenyi;An, Elvira;Okeke, Ifunanya;Zheng, Sijin;Luo, Xuanmeng;Gong, Angela;Jaime-Figueroa, Saul;Crews, Craig M.
蛋白质的磷酸化，调节细胞生物学的许多关键方面，是由激酶和磷酸酶动态控制的。许多疾病与关键蛋白的异常过度磷酸化有关，例如癌症中的视网膜母细胞瘤蛋白。虽然激酶抑制剂已经在临床上得到了广泛的应用，但越来越多的证据表明，非靶点效应和不断增加的耐药性促使人们有必要开发新一代药物。在这里，我们提出了一项针对嵌合体的磷酸化的概念验证研究(PhosTACs)。与PROTAC在诱导三元复合体的能力上相似，PhosTAC专注于将Ser/Thr磷酸酶招募到磷酸底物上，以介导其去磷酸化。然而，与PROTAC不同的是，PhosTAC可以提供独特的靶向功能获得机会来操纵蛋白质的活性。在这项研究中，我们应用化学生物学的方法来评估PhosTACs的可行性，方法是将PP2A全酶的支架和催化亚基重新招募到PDCD4和FOXO3a等蛋白质底物上进行靶向蛋白质去磷酸化。对于FOXO3a，这种去磷酸化导致了FOXO3a反应报告基因的转录激活。
Protein phosphorylation, which regulates many critical aspects of cell biology, is dynamically governed by kinases and phosphatases. Many diseases are associated with dysregulated hyperphosphorylation of critical proteins, such as retinoblastoma protein in cancer. Although kinase inhibitors have been widely applied in the clinic, growing evidence of off-target effects and increasing drug resistance prompts the need to develop a new generation of drugs. Here, we propose a proof-of-concept study of Phosphorylation TArgeting Chimeras (PhosTACs). Similar to PROTACs in their ability to induce ternary complexes, PhosTACs focus on recruiting a Ser/Thr phosphatase to a phosphosubstrate to mediate its dephosphorylation. However, distinct from PROTACs, PhosTACs can uniquely provide target gain-of-function opportunities to manipulate protein activity. In this study, we applied a chemical biology approach to evaluate the feasibility of PhosTACs by recruiting the scaffold and catalytic subunits of the PP2A holoenzyme to protein substrates such as PDCD4 and FOXO3a for targeted protein dephosphorylation. For FOXO3a, this dephosphorylation resulted in transcriptional activation of a FOXO3a-responsive reporter gene.
登录
查看更多内容
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1007/978-1-62703-562-0_17
发表时间：
2013-01-01
期刊：
PHOSPHATASE MODULATORS
影响因子：
--
作者：
Lambrecht, Caroline;Haesen, Dorien;Janssens, Veerle
通讯作者：
Janssens, Veerle
影响因子：
11.4
作者：
Rena, G;Woods, YL;Cohen, P
通讯作者：
Cohen, P
影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
16.6
作者：
Hart GW;Slawson C;Ramirez-Correa G;Lagerlof O
通讯作者：
Lagerlof O