Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex.
Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex.
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DOI：
10.1038/s41598-018-34605-2
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发表时间：
2018-11-07
影响因子：
4.6
通讯作者：
Kidera A
中科院分区：
文献类型：
--
作者：
Moritsugu K;Nishi H;Inariyama K;Kobayashi M;Kidera A
多聚泛素（poly-Ub）通过对Ub结合域（UBD）的连接特异性识别参与多种细胞过程。在这项研究中，使用分子动力学（MD）模拟与增强的采样方法，我们证明了K63连接的二Ub识别TAB 2的NZF结构域，锌指UBD，在一个高度动态的结构，从UBD和连接两个Ub的柔性接头之间的弱相互作用形成的合奏。然而，K63 di-Ub/TAB 2 NZF复合物显示出比非天然复合物线性di-Ub/TAB 2 NZF和K33 di-Ub/TAB 2 NZF更紧凑和稳定的系综，线性di-Ub/HOIL-1 L NZF和K33 di-Ub/TRABID NZF 1分别是从线性di-Ub/HOIL-1 L NZF和K33 di-Ub/TAB 2 NZF建模的。我们通过将Ub连接从天然K63改变为四种不同的非天然连接（线性、K6、K11和K48），同时保持天然复合物中的分子间接触，进一步证明了K63 di-Ub/TAB 2 NZF MD模拟结果中Ub-Ub连接体的长度和位置的重要性。具有非本机链接的系统都不维护本机绑定配置。这些模拟结果提供了一个原子图像的连接特异性识别的poly-Ubs导致的生物功能，如细胞共定位的各种组分蛋白质的信号转导途径。
Poly-ubiquitin (poly-Ub) is involved in various cellular processes through the linkage-specific recognition of Ub-binding domains (UBD). In this study, using molecular dynamics (MD) simulation together with an enhanced sampling method, we demonstrated that K63-linked di-Ub recognizes the NZF domain of TAB2, a zinc finger UBD, in an ensemble of highly dynamic structures that form from the weak interactions between UBD and the flexible linker connecting the two Ubs. However, the K63 di-Ub/TAB2 NZF complex showed a much more compact and stable ensemble than the non-native complexes, linear di-Ub/TAB2 NZF and K33 di-Ub/TAB2 NZF, that were modeled from linear di-Ub/HOIL-1L NZF and K33 di-Ub/TRABID NZF1, respectively. We further demonstrated the importance of the length and position of the Ub-Ub linker in the results of MD simulations of K63 di-Ub/TAB2 NZF by changing the Ub linkage from the native K63 to four different non-native linkages, linear, K6, K11, and K48, while maintaining inter-molecular contacts in the native complex. No systems with non-native linkage maintained the native binding configuration. These simulation results provide an atomistic picture of the linkage specific recognition of poly-Ubs leading to the biological functions such as cellular colocalization of various component proteins in the signal transduction pathways.
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影响因子：
2.4
作者：
Morishita, Tetsuya;Itoh, Satoru G.;Mikami, Masuhiro
通讯作者：
Mikami, Masuhiro
影响因子：
3
作者：
Ikeguchi, M
通讯作者：
Ikeguchi, M
影响因子：
4.4
作者：
Fukunishi, H;Watanabe, O;Takada, S
通讯作者：
Takada, S
影响因子：
11.4
作者：
Alam, SL;Sun, J;Sundquist, WI
通讯作者：
Sundquist, WI
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.