The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Institute of Structural and Molecular Biology, University College London, London WC1E 6XA, UK.
Nucleic Acids Res. 2018 Apr 20;46(7):3802-3812. doi: 10.1093/nar/gky199.
The multi-protein complex WRAD, formed by WDR5, RbBP5, Ash2L and Dpy30, binds to the MLL SET domain to stabilize the catalytically active conformation required for histone H3K4 methylation. In addition, the WRAD complex contributes to the targeting of the activated complex to specific sites on chromatin. RbBP5 is central to MLL catalytic activation, by making critical contacts with the other members of the complex. Interestingly its only major structural domain, a canonical WD40 repeat β-propeller, is not implicated in this function. Here, we present the structure of the RbBP5 β-propeller domain revealing a distinct, feature rich surface, dominated by clusters of Arginine residues. Our nuclear magnetic resonance binding data supports the hypothesis that in addition to the role of RbBP5 in catalytic activation, its β-propeller domain is a platform for the recruitment of the MLL complexes to chromatin targets through its direct interaction with nucleic acids.
WRAD 多蛋白复合物由 WDR5、RbBP5、Ash2L 和 Dpy30 组成，与 MLL SET 结构域结合，稳定催化活性构象，从而促进组蛋白 H3K4 甲基化。此外，WRAD 复合物有助于将激活的复合物靶向染色质上的特定位置。RbBP5 通过与复合物的其他成员形成关键接触，对 MLL 催化激活至关重要。有趣的是，它唯一的主要结构域——经典 WD40 重复β-三叶因子，与该功能无关。在此，我们呈现了 RbBP5β-三叶因子结构域的结构，揭示了一个独特的、富含特征的表面，主要由精氨酸簇组成。我们的核磁共振结合数据支持了这样一种假设，即除了在催化激活中的作用之外，RbBP5 的β-三叶因子结构域还是一个平台，通过与核酸的直接相互作用，将 MLL 复合物招募到染色质靶标上。
