Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation
Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation
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DOI：
10.1016/j.cell.2009.03.007
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发表时间：
2009-03-20
期刊：
影响因子：
64.5
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
--
作者：
Rahighi, Simin;Ikeda, Fumiyo;Dikic, Ivan
核因子-κ B（NF-κ B）是免疫诱导转录的关键介质，其激活需要NF-κ B必需调节因子（NEMO）与泛素化底物的结合。在这里，我们报告说，UBAN（泛素结合ABIN和NEMO）基序的NEMO选择性地结合线性（头到尾）泛素链。UBAN基序的晶体结构揭示了平行卷曲螺旋二聚体，其与两个线性双泛素分子形成异四聚体复合物。UBAN二聚体接触所有四个泛素部分，并且每个结合位点的完整性是有效的NF-κ B活化所必需的。通过近端泛素部分上的表面和远端部分上的典型Ile 44表面发生结合，从而提供线性链识别的特异性。参与结合线性泛素链的NEMO残基是TNF-α和其他激动剂激活NF-κ B所必需的，这为NEMO突变在患有X连锁外胚层发育不良和免疫缺陷的患者中的有害作用提供了解释。
Activation of nuclear factor-kappa B (NF-kappa B), a key mediator of inducible transcription in immunity, requires binding of NF-kappa B essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-kappa B activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-kappa B activation by TNF-alpha and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency.