Ubiquitin ligase TRAF6, together with ubiquitin-conjugating enzyme Ubc13/Uev1, catalyzes processive assembly of unanchored K63-linked polyubiquitin chains for TAK1 activation in the IL-1R/TLR pathways. However, what domain and how it functions to enable TRAF6's processivity are largely uncharacterized. Here, we find TRAF6 coiled-coil (CC) domain is crucial to enable its processivity. The CC domain mediates TRAF6 oligomerization to ensure efficient long polyubiquitin chain assembly. Mutating or deleting the CC domain impairs TRAF6 oligomerization and processive polyubiquitin chain assembly. Fusion of the CC domain to the E3 ubiquitin ligase CHIP/STUB1 renders the latter capable of NF-κB activation. Moreover, the CC domain, after oligomerization, interacts with Ubc13/Ub~Ubc13, which further contributes to TRAF6 processivity. Point mutations within the CC domain that weaken TRAF6 interaction with Ubc13/Ub~Ubc13 diminish TRAF6 processivity. Our results reveal that the CC oligomerization primes its interaction with Ubc13/Ub~Ubc13 to confer processivity to TRAF6 ubiquitin ligase activity.Ubiquitin ligase TRAF6 catalyzes assembly of free polyubiquitin chains for TAK1 activation in the IL-1R/TLR pathways, but the mechanism underlying its processivity is unclear. Here, the authors show that TRAF6 coiled-coil oligomerization domain primes its interaction with Ubc13/Ub~Ubc13 to confer processivity.

中文翻译：

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与Ubc13齐聚引发的卷曲螺旋结构域相互作用赋予TRAF6泛素连接酶活性以持续性。

泛素连接酶TRAF6与泛素结合酶Ubc13 / Uev1共同催化未锚定K63连接的多泛素链的过程性装配，以激活IL-1R / TLR途径中的TAK1。但是，什么领域以及如何发挥作用以实现TRAF6的生产力，目前尚无定论。在这里，我们发现TRAF6螺旋线圈（CC）域对于使其具有连续性至关重要。CC域介导TRAF6寡聚化，以确保有效的长泛素链长组装。突变或删除CC域损害TRAF6寡聚和进行性多聚泛素链组装。CC结构域与E3泛素连接酶CHIP / STUB1的融合使后者能够进行NF-κB激活。此外，低聚后的CC结构域与Ubc13 / Ub〜Ubc13相互作用，这进一步有助于TRAF6的合成能力。CC域内的点突变削弱了TRAF6与Ubc13 / Ub〜Ubc13的相互作用，从而降低了TRAF6的合成能力。我们的研究结果表明CC寡聚化可引发其与Ubc13 / Ub〜Ubc13的相互作用，从而赋予TRAF6泛素连接酶活性以持续性。其生产能力尚不清楚。在此，作者表明TRAF6卷曲螺旋低聚结构域引发了其与Ubc13 / Ub〜Ubc13的相互作用，从而赋予了合成能力。泛素连接酶TRAF6催化IL-1R / TLR途径中TAK1活化的自由多聚泛素链的组装，但其过程性机制尚不清楚。在此，作者表明TRAF6卷曲螺旋低聚结构域引发了其与Ubc13 / Ub〜Ubc13的相互作用，从而赋予了合成能力。泛素连接酶TRAF6催化IL-1R / TLR途径中TAK1活化的自由多聚泛素链的组装，但其过程性机制尚不清楚。在此，作者表明TRAF6卷曲螺旋低聚结构域引发了其与Ubc13 / Ub〜Ubc13的相互作用，从而赋予了合成能力。