Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
J Mol Biol. 2021 Apr 16;433(8):166844. doi: 10.1016/j.jmb.2021.166844. Epub 2021 Feb 2.
Tumour necrosis factor (TNF) receptor associated factor (TRAF) family members share a common domain architecture, but play non-redundant physiological roles in cell signalling. At the N terminus, most TRAFs have a RING domain, followed by a series of Zinc finger (ZF) domains. The RING domain of TRAF6 dimerizes, and the RING homodimer together with the first ZF assembles ubiquitin chains that form a platform which facilitates activation of downstream kinases. The RING dimer interface is conserved amongst TRAF proteins, suggesting that functional heterodimers could be possible. Here we report the structure of the TRAF5-TRAF6 RING heterodimer, which accounts for the stability of the heterodimer as well as its ability to assemble ubiquitin chains. We also show that the RING domain of TRAF6 heterodimerizes with TRAF3 and TRAF2, and demonstrate that the linker helix and first ZF of TRAF2 can cooperate with TRAF6 to promote chain assembly. Collectively our results suggest that TRAF RING homo- and hetero-dimers have the potential to bridge interaction of nearby TRAF trimers and modulate TRAF-mediated signalling.
肿瘤坏死因子（TNF）受体相关因子（TRAF）家族成员具有共同的结构域架构，但在细胞信号转导中发挥非冗余的生理作用。在 N 端，大多数 TRAFs 具有 RING 结构域，其后是一系列锌指（ZF）结构域。TRAF6 的 RING 结构域形成二聚体，RING 同源二聚体与第一个 ZF 一起组装泛素链，形成一个平台，促进下游激酶的激活。TRAF 蛋白之间的 RING 二聚体界面是保守的，这表明功能性异源二聚体是可能的。在这里，我们报告了 TRAF5-TRAF6 RING 异源二聚体的结构，该结构解释了异源二聚体的稳定性及其组装泛素链的能力。我们还表明，TRAF6 的 RING 结构域与 TRAF3 和 TRAF2 形成异源二聚体，并证明 TRAF2 的连接螺旋和第一个 ZF 可以与 TRAF6 合作促进链组装。总之，我们的结果表明，TRAF RING 同型和异型二聚体有可能桥接附近 TRAF 三聚体的相互作用，并调节 TRAF 介导的信号转导。
