Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity.
Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity.
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DOI：
10.15252/embj.201593741
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发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Rittinger K
中科院分区：
文献类型：
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作者：
Koliopoulos MG;Esposito D;Christodoulou E;Taylor IA;Rittinger K
TRIM E3泛素连接酶调节多种细胞过程，并且在先天免疫信号传导事件期间特别重要。它们的特征在于其N末端部分的保守三联基序，其包含典型的RING结构域、一个或两个B-盒结构域和介导连接酶二聚化的卷曲螺旋区。通过卷曲螺旋的自缔合被认为是TRIM催化活性的关键;然而，这一观察结果背后的精确分子机制仍然难以捉摸。在这里，我们提供了一个详细的TRIM连接酶TRIM 25和TRIM 32的特性，并显示它们的寡聚状态是如何连接到催化活性。TRIM 25 RING结构域和负载泛素的E2之间的复合物的晶体结构确定了促进闭合E2~Ub构象以激活硫酯用于泛素转移的结构和机制特征，使我们能够提出全长蛋白质活性调节的模型。我们的数据揭示了TRIMs自缔合机制的意外多样性，这可能对其生物功能至关重要。
TRIM E3 ubiquitin ligases regulate a wide variety of cellular processes and are particularly important during innate immune signalling events. They are characterized by a conserved tripartite motif in their N‐terminal portion which comprises a canonical RING domain, one or two B‐box domains and a coiled‐coil region that mediates ligase dimerization. Self‐association via the coiled‐coil has been suggested to be crucial for catalytic activity of TRIMs; however, the precise molecular mechanism underlying this observation remains elusive. Here, we provide a detailed characterization of the TRIM ligases TRIM25 and TRIM32 and show how their oligomeric state is linked to catalytic activity. The crystal structure of a complex between the TRIM25 RING domain and an ubiquitin‐loaded E2 identifies the structural and mechanistic features that promote a closed E2~Ub conformation to activate the thioester for ubiquitin transfer allowing us to propose a model for the regulation of activity in the full‐length protein. Our data reveal an unexpected diversity in the self‐association mechanism of TRIMs that might be crucial for their biological function.