The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension.
The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension.
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DOI：
10.1038/emboj.2012.217
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发表时间：
2012-10-03
期刊：
影响因子：
11.4
通讯作者：
Sixma, Titia K.
中科院分区：
文献类型：
--
作者：
Smit, Judith J.;Monteferrario, Davide;Noordermeer, Sylvie M.;van Dijk, Willem J.;van der Reijden, Bert A.;Sixma, Titia K.
NF-κB通路的激活需要在NEMO上形成Met 1连接的“线性”泛素链，这是由HOIP、HOIL-1 L和Sharpin组成的线性泛素链组装复合物（LUBAC）E3催化的。在这里，我们表明，LUBAC的催化活性和LUBAC的线性泛素链形成的特异性嵌入在环-IBR-环（RBR）泛素连接酶亚基HOIP。线性泛素链的形成HOIP通过两步机制进行，涉及RING和HECT E3型活动。RING 1-IBR催化泛素从E2转移到RING 2上，以瞬时形成HECT样共价硫酯中间体。接着，将泛素从HOIP转移到靶泛素的N-末端。这种转移是由HOIP的C-末端的一个独特区域促进的，我们称之为“线性泛素链决定结构域”（LDD），它可以与受体泛素协调。与该机制一致，在细胞测定中发现RING 2-LDD区域对于NF-κB活化是重要的。这些数据显示HOIP如何将一般RBR泛素连接酶机制与独特的LDD依赖性特异性结合以产生线性泛素链。
Activation of the NF-κB pathway requires the formation of Met1-linked ‘linear’ ubiquitin chains on NEMO, which is catalysed by the Linear Ubiquitin Chain Assembly Complex (LUBAC) E3 consisting of HOIP, HOIL-1L and Sharpin. Here, we show that both LUBAC catalytic activity and LUBAC specificity for linear ubiquitin chain formation are embedded within the RING-IBR-RING (RBR) ubiquitin ligase subunit HOIP. Linear ubiquitin chain formation by HOIP proceeds via a two-step mechanism involving both RING and HECT E3-type activities. RING1-IBR catalyses the transfer of ubiquitin from the E2 onto RING2, to transiently form a HECT-like covalent thioester intermediate. Next, the ubiquitin is transferred from HOIP onto the N-terminus of a target ubiquitin. This transfer is facilitated by a unique region in the C-terminus of HOIP that we termed ‘Linear ubiquitin chain Determining Domain’ (LDD), which may coordinate the acceptor ubiquitin. Consistent with this mechanism, the RING2-LDD region was found to be important for NF-κB activation in cellular assays. These data show how HOIP combines a general RBR ubiquitin ligase mechanism with unique, LDD-dependent specificity for producing linear ubiquitin chains.
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