Allosteric regulation of E2:E3 interactions promote a processive ubiquitination machine
Allosteric regulation of E2:E3 interactions promote a processive ubiquitination machine
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DOI：
10.1038/emboj.2013.174
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发表时间：
2013-09-11
期刊：
影响因子：
11.4
通讯作者：
Byrd, R. Andrew
中科院分区：
文献类型：
--
作者：
Das, Ranabir;Liang, Yu-He;Byrd, R. Andrew
环指蛋白构成了泛素连接酶（E3）的绝大多数，并通过与带有泛素的泛素缀合酶（E2）相互作用发挥功能。低亲和力RING-E2相互作用如何导致高度进行性底物泛素化在很大程度上是未知的。RING E3，gp 78是研究这一过程的极好模型。gp 78包括与其同源物E2、Ube 2g 2、G2 BR的高亲和力二级结合区。G2 BR变构增强RING：Ube 2g 2结合和泛素化。RING：Ube 2g 2：G2 BR复合物的结构分析揭示，在RING：Ube 2g 2界面处G2 BR诱导的构象效应对于RING与Ube 2g 2或Ube 2g 2与Ub缀合的增强结合是必需的。这种构象效应和与缀合泛素的关键三元相互作用是泛素转移所必需的。此外，RING：Ube 2g 2结合诱导第二变构效应，破坏Ube 2g 2：G2 BR接触，降低亲和力并促进E2交换。因此，gp 78是一个泛素化机器，其中多个E2结合位点协调地促进进行性泛素化。
RING finger proteins constitute the large majority of ubiquitin ligases (E3s) and function by interacting with ubiquitin-conjugating enzymes (E2s) charged with ubiquitin. How low-affinity RING-E2 interactions result in highly processive substrate ubiquitination is largely unknown. The RING E3, gp78, represents an excellent model to study this process. gp78 includes a high-affinity secondary binding region for its cognate E2, Ube2g2, the G2BR. The G2BR allosterically enhances RING: Ube2g2 binding and ubiquitination. Structural analysis of the RING: Ube2g2:G2BR complex reveals that a G2BR-induced conformational effect at the RING: Ube2g2 interface is necessary for enhanced binding of RING to Ube2g2 or Ube2g2 conjugated to Ub. This conformational effect and a key ternary interaction with conjugated ubiquitin are required for ubiquitin transfer. Moreover, RING: Ube2g2 binding induces a second allosteric effect, disrupting Ube2g2: G2BR contacts, decreasing affinity and facilitating E2 exchange. Thus, gp78 is a ubiquitination machine where multiple E2-binding sites coordinately facilitate processive ubiquitination.