Molecular basis for the unique deubiquitinating activity of the NF-κB inhibitor A20
Molecular basis for the unique deubiquitinating activity of the NF-κB inhibitor A20
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DOI：
10.1016/j.jmb.2007.11.092
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发表时间：
2008-02-15
影响因子：
5.6
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Lin, Su-Chang;Chung, Jee Y.;Wu, Hao
肿瘤坏死因子、白细胞介素-1和Toll样受体通路中的核因子κ B（NF-κ B）活化需要Lys 63连接的非降解性多聚泛素化。A20是这些通路中NF-κ B活化的特异性反馈抑制剂，具有双重泛素编辑功能。A20的N端结构域是一种去泛素化酶（DUB），用于Lys 63连接的多聚泛素化信号传导介质，如TRAF 6和RIP，其C端结构域是一种泛素连接酶（E3），用于相同底物的Lys 48连接的降解性多聚泛素化。为了阐明A20的DUB活性的分子基础，我们确定了其晶体结构，并进行了一系列的生化和细胞生物学研究。该结构揭示了A20的潜在催化机制，可能与木瓜蛋白酶样半胱氨酸蛋白酶显著不同。泛素可以对接到一个保守的A20表面，这种相互作用表现出电荷互补性，没有空间冲突。令人惊讶的是，A20对Lys 63连接的多聚泛素链没有特异性。相反，它有效地从TRAF 6中去除了Lys 63连接的多聚泛素链，而不分解链本身。我们的研究表明，A20并不作为一个一般的DU B，但具有特定的多聚泛素化底物的特异性，以确保其在调节肿瘤坏死因子，白细胞介素-1和Toll样受体途径中NF-κ B活化的保真度。(C)2007爱思唯尔有限公司版权所有。
Nuclear factor kappa B (NF-kappa B) activation in tumor necrosis factor, interleukin-1, and Toll-like receptor pathways requires Lys63-linked nondegradative polyubiquitination. A20 is a specific feedback inhibitor of NF-kappa B activation in these pathways that possesses dual ubiquitin-editing functions. While the N-terminal domain of A20 is a deubiquitinating enzyme (DUB) for Lys63-linked polyubiquitinated signaling mediators such as TRAF6 and RIP, its C-terminal domain is a ubiquitin ligase (E3) for Lys48-linked degradative polyubiquitination of the same substrates. To elucidate the molecular basis for the DUB activity of A20, we determined its crystal structure and performed a series of biochemical and cell biological studies. The structure reveals the potential catalytic mechanism of A20, which may be significantly different from papain-like cysteine proteases. Ubiquitin can be docked onto a conserved A20 surface; this interaction exhibits charge complementarity and no steric clash. Surprisingly, A20 does not have specificity for Lys63-linked polyubiquitin chains. Instead, it effectively removes Lys63-linked polyubiquitin chains from TRAF6 without dissembling the chains themselves. Our studies suggest that A20 does not act as a general DUB but has the specificity for particular polyubiquitinated substrates to assure its fidelity in regulating NF-kappa B activation in the tumor necrosis factor, interleukin-1, and Toll-like receptor pathways. (C) 2007 Elsevier Ltd. All rights reserved.