E2 Partner Tunes the Ubiquitylation Specificity of Arkadia E3 Ubiquitin Ligase.
E2 Partner Tunes the Ubiquitylation Specificity of Arkadia E3 Ubiquitin Ligase.
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作者：
泛素介导的蛋白酶体降解是控制蛋白质细胞浓度的基本和紧密协调的过程。E3泛素连接酶负责底物识别，其失调与各种疾病相关，最显著的是癌症。E3连接酶Arkadia（RNF 111）靶向TGF-β SMAD 2/3信号通路的蛋白酶体降解负调节因子和聚SUMO化蛋白，例如，早幼粒细胞白血病蛋白。在此，我们提供了有价值的见解Arkadia与其生理E2伙伴，UbcH 5 B和UbcH 13，以及UbcH 7的相互作用和功能。具体来说，我们确定了这些E2酶和Arkadia的关键氨基酸残基，它们的配对和Arkadia的泛素化机制的酶活性的控制是必不可少的。我们的研究结果丰富了目前对泛素化系统关键组分的认识，并可以成为未来药物开发的基础。Arkadia（RNF 111）是TGF-β信号传导的正调节因子，介导该途径的负因子的蛋白酶体依赖性降解。它被分类为E3泛素连接酶和SUMO靶向泛素连接酶（STUBL），涉及各种病理条件，包括癌症和纤维化。Arkadia的酶（连接酶）活性位于其C-末端，涉及RING结构域。值得注意的是，E3连接酶需要E2酶来进行泛素化。然而，Arkadia与各种E2酶的合作以及它们介导的泛素化类型知之甚少。在目前的工作中，我们研究了Arkadia与E2合作伙伴UbcH 5 B和UbcH 13以及UbcH 7的相互作用。通过NMR光谱，我们发现E2-Arkadia相互作用表面在所有检查的对中是相似的。尽管如此，确定酶活性E2-Arkadia复合物的要求和因素在每种情况下都不同。此外，我们揭示了Arkadia与不同E2的合作导致通过K63，K48或K11连接形成单泛素化或聚泛素链，这可以决定底物的命运并导致不同的生物学结果。
Ubiquitin-mediated proteasomal degradation is a fundamental and tightly coordinated process that controls the cellular concentration of proteins. E3 ubiquitin ligases are responsible for substrate recognition, and their deregulation is associated with various diseases, most notably, cancer. The E3 ligase Arkadia (RNF111) targets for proteasomal degradation negative regulators of the TGF-β SMAD2/3 signaling pathway and poly-SUMOylated proteins, e.g., promyelocytic leukemia protein. Herein, we provide valuable insights into the interaction and function of Arkadia with its physiological E2 partners, UbcH5Β and UbcH13, as well as UbcH7. Specifically, we identify key amino acid residues on these E2 enzymes and Arkadia that are essential for their pairing and control of the enzymatic activity of Arkadia in ubiquitylation machinery. Our findings enrich the current knowledge on the pivotal components of the ubiquitylation system and can be the basis for future drug development. Arkadia (RNF111) is a positive regulator of the TGF-β signaling that mediates the proteasome-dependent degradation of negative factors of the pathway. It is classified as an E3 ubiquitin ligase and a SUMO-targeted ubiquitin ligase (STUBL), implicated in various pathological conditions including cancer and fibrosis. The enzymatic (ligase) activity of Arkadia is located at its C-terminus and involves the RING domain. Notably, E3 ligases require E2 enzymes to perform ubiquitylation. However, little is known about the cooperation of Arkadia with various E2 enzymes and the type of ubiquitylation that they mediate. In the present work, we study the interaction of Arkadia with the E2 partners UbcH5B and UbcH13, as well as UbcH7. Through NMR spectroscopy, we found that the E2–Arkadia interaction surface is similar in all pairs examined. Nonetheless, the requirements and factors that determine an enzymatically active E2–Arkadia complex differ in each case. Furthermore, we revealed that the cooperation of Arkadia with different E2s results in either monoubiquitylation or polyubiquitin chain formation via K63, K48, or K11 linkages, which can determine the fate of the substrate and lead to distinct biological outcomes.
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影响因子：
5.6
作者：
Birkou, Maria;Delegkou, Georgia N.;Marousis, Konstantinos D.;Fragkaki, Nefeli;Toro, Tamara;Episkopou, Vasso;Spyroulias, Georgios A.
通讯作者：
Spyroulias, Georgios A.
影响因子：
2.9
作者：
Haldeman, MT;Xia, G;Pickart, CM
通讯作者：
Pickart, CM
影响因子：
4.8
作者：
Baboshina, OV;Haas, AL
通讯作者：
Haas, AL
影响因子：
3.5
作者：
Häkli, M;Lorick, KL;Palvimo, JJ
通讯作者：
Palvimo, JJ
影响因子：
64.5
作者：
Chan CH;Morrow JK;Li CF;Gao Y;Jin G;Moten A;Stagg LJ;Ladbury JE;Cai Z;Xu D;Logothetis CJ;Hung MC;Zhang S;Lin HK
通讯作者：
Lin HK