Bmi1/Ring1b 泛素连接酶复合物对 UbcH5c 和核小体的识别。
Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex.
机构信息
Department of Early Discovery Biochemistry, Genentech Research and Early Development, South San Francisco, CA, USA.
出版信息
EMBO J. 2011 Jul 19;30(16):3285-97. doi: 10.1038/emboj.2011.243.
The Polycomb repressive complex 1 (PRC1) mediates gene silencing, in part by monoubiquitination of histone H2A on lysine 119 (uH2A). Bmi1 and Ring1b are critical components of PRC1 that heterodimerize via their N-terminal RING domains to form an active E3 ubiquitin ligase. We have determined the crystal structure of a complex between the Bmi1/Ring1b RING-RING heterodimer and the E2 enzyme UbcH5c and find that UbcH5c interacts with Ring1b only, in a manner fairly typical of E2-E3 interactions. However, we further show that the Bmi1/Ring1b RING domains bind directly to duplex DNA through a basic surface patch unique to the Bmi1/Ring1b RING-RING dimer. Mutation of residues on this interaction surface leads to a loss of H2A ubiquitination activity. Computational modelling of the interface between Bmi1/Ring1b-UbcH5c and the nucleosome suggests that Bmi1/Ring1b interacts with both nucleosomal DNA and an acidic patch on histone H4 to achieve specific monoubiquitination of H2A. Our results point to a novel mechanism of substrate recognition, and control of product formation, by Bmi1/Ring1b.
多梳抑制复合物 1（PRC1）介导基因沉默，部分通过组蛋白 H2A 赖氨酸 119 的单泛素化（uH2A）实现。Bmi1 和 Ring1b 是 PRC1 的关键组成部分，它们通过其 N 端 RING 结构域异二聚化形成活性 E3 泛素连接酶。我们已经确定了 Bmi1/Ring1b RING-RING 异二聚体与 E2 酶 UbcH5c 之间复合物的晶体结构，发现 UbcH5c 仅与 Ring1b 相互作用，这种方式相当典型的 E2-E3 相互作用。然而，我们进一步表明，Bmi1/Ring1b RING 结构域通过 Bmi1/Ring1b RING-RING 二聚体特有的碱性表面斑块直接与双链 DNA 结合。该相互作用表面上残基的突变导致 H2A 泛素化活性丧失。Bmi1/Ring1b-UbcH5c 和核小体之间界面的计算模型表明，Bmi1/Ring1b 与核小体 DNA 和组蛋白 H4 上的酸性斑块相互作用，以实现 H2A 的特异性单泛素化。我们的结果指出了 Bmi1/Ring1b 识别底物和控制产物形成的新机制。
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