Characterization of COMMD protein-protein interactions in NF-κB signalling
Characterization of COMMD protein-protein interactions in NF-κB signalling
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DOI：
10.1042/bj20051664
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发表时间：
2006-08-15
影响因子：
4.1
通讯作者：
Klomp, Leo W. J.
中科院分区：
文献类型：
--
作者：
de Bie, Prim;van de Sluis, Bart;Klomp, Leo W. J.
COMMD [铜代谢基因 MURR1（小鼠 U2af1-rs1 区域 1）结构域] 蛋白构成了最近鉴定的 NF-kappa B（核因子 kappa B）抑制蛋白家族，其特征是存在 COMM 结构域。在本文中，我们通过对涉及 COMMD 蛋白的蛋白质-蛋白质相互作用的表征，详细研究了该蛋白质家族的作用，特别是 COMM 结构域在 NF-kappa B 信号传导中的作用。普遍表达的小型 COMMD6 主要由 COMM 结构域组成。因此，COMMD1 和 COMMD6 作为 COMMD 蛋白家族的原型成员进行了进一步分析。使用特定的抗血清，描述了内源性 COMMD1 和 COMMD6 之间的相互作用。这种相互作用通过独立技术得到验证，似乎是直接的，并且可以在整个细胞（包括细胞核）中检测到。两种蛋白均以非协同方式抑制 TNF（肿瘤坏死因子）诱导的 NF-κ B 激活。 COMMD6 COMM 结构域中氨基酸残基 Trp(24) 和 Pro(41) 的突变完全消除了 COMMD6 对 TNF 诱导的 NF-κ B 激活的抑制作用，但这并不伴随着与 COMMD I、COMMD6 或 NF-κ B 亚基 RelA 相互作用的丧失。与 COMMD1 相比，COMMD6 不与 I kappa B α（抑制性 kappa B α）结合，表明两种蛋白以重叠但不完全相似的方式抑制 NF-kappa B。总而言之，这些数据支持了 COMMD 蛋白质-蛋白质相互作用的重要性，并为该蛋白质家族在 NF-κ B 信号传导中的功能提供了新的机制见解。
COMMD [copper metabolism gene MURR1 (mouse U2af1-rs1 region 1) domain] proteins constitute a recently identified family of NF-kappa B (nuclear factor kappa B)-inhibiting proteins, characterized by the presence of the COMM domain. In the present paper, we report detailed investigation of the role of this protein family, and specifically the role of the COMM domain, in NF-kappa B signalling through characterization of protein-protein interactions involving COMMD proteins. The small ubiquitously expressed COMMD6 consists primarily of the COMM domain. Therefore COMMD1 and COMMD6 were analysed further as prototype members of the COMMD protein family. Using specific antisera, interaction between endogenous COMMD1 and COMMD6 is described. This interaction was verified by independent techniques, appeared to be direct and could be detected throughout the whole cell, including the nucleus. Both proteins inhibit TNF (tumour necrosis factor)-induced NF-kappa B activation in a non-synergistic manner. Mutation of the amino acid residues Trp(24) and Pro(41) in the COMM domain of COMMD6 completely abolished the inhibitory effect of COMMD6 on TNF-induced NF-kappa B activation, but this was not accompanied by loss of interaction with COMMD I, COMMD6 or the NF-kappa B subunit RelA. In contrast with COMMD1, COMMD6 does not bind to I kappa B alpha (inhibitory kappa B alpha), indicating that both proteins inhibit NF-kappa B in an overlapping, but not completely similar, manner. Taken together, these data support the significance of COMMD protein-protein interactions and provide new mechanistic insight into the function of this protein family in NF-kappa B signalling.