Li Yanjun, Okatsu Kei, Fukai Shuya, Sato Yusuke
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan.
Biophys J. 2021 Aug 17;120(16):3355-3362. doi: 10.1016/j.bpj.2021.06.037. Epub 2021 Jul 7.
TAK1-binding protein 2 (TAB2) has generally been considered to bind specifically to K63-linked polyubiquitin chains via its C-terminal Npl4 zinc-finger (NZF) domain. However, a recent study showed that the NZF domain of TAB2 (TAB2-NZF) could also interact with K6-linked polyubiquitin chains. Here, we report the crystal structure of TAB2-NZF in complex with K6-linked diubiquitin (K6-Ub) at 1.99-Å resolution. TAB2-NZF simultaneously interacts with the distal and proximal ubiquitin moieties of K6-Ub. By comparing the structures of TAB2-NZF in complex with K6-Ub and with K63-linked diubiquitin (K63-Ub), we reveal that the binding mechanism of TAB2-NZF with K6-Ub is similar to that with K63-Ub, except for the flexible C-terminal region of the distal ubiquitin. Therefore, we conclude that the C-terminal flexibility of the distal ubiquitin contributes to the dual specificity of TAB2-NZF toward K6- and K63-linked ubiquitin chains. This study provides important insights into the functions of K6-linked ubiquitin chains, which are currently unclear.
TAK1结合蛋白2（TAB2）通常被认为通过其C末端的Npl4锌指（NZF）结构域特异性结合K63连接的多聚泛素链。然而，最近的一项研究表明，TAB2的NZF结构域（TAB2-NZF）也能与K6连接的多聚泛素链相互作用。在此，我们报告了TAB2-NZF与K6连接的双泛素（K6-Ub）复合物的晶体结构，分辨率为1.99 Å。TAB2-NZF同时与K6-Ub的远端和近端泛素部分相互作用。通过比较TAB2-NZF与K6-Ub以及与K63连接的双泛素（K63-Ub）复合物的结构，我们发现除了远端泛素的柔性C末端区域外，TAB2-NZF与K6-Ub的结合机制与与K63-Ub的相似。因此，我们得出结论，远端泛素的C末端柔性有助于TAB2-NZF对K6和K63连接的泛素链的双重特异性。这项研究为目前尚不清楚的K6连接的泛素链的功能提供了重要见解。
