法国斯特拉斯堡大学Adam Ben-Shem团队近期取得重要工作进展。他们报道了人TIP60-C组蛋白交换和乙酰转移酶复合物的结构。相关论文于2024年9月11日发表于国际顶尖学术期刊《自然》杂志上。

据介绍，染色质结构是DNA转录、复制和修复的关键调节因子。在人类中，TIP60/EP400复合物（TIP60-C）是一个由20个亚基组成的组装体，通过两种酶活性影响染色质结构：组蛋白H2A/H2B与H2A的ATP依赖性交换。Z/H2B和组蛋白乙酰化，在酵母中分别由两个独立的复合物SWR1和NuA4进行。这些活动如何在人类中合并成一个超级复合体，以及这种关联对它们的结构、机制和染色质的招募意味着什么，目前尚不清楚。

研究人员描述了内源性人类TIP60-C的2.4-3.3Å分辨率结构，发现了一种由SWR1样（SWR1L）和NuA4样（NuA4L）部分组成的三瓣结构，与TRRAP激活剂结合模块有关。巨大的EP400亚基含有ATP酶马达，穿过SWR1L和NuA4L之间的两倍连接，构成三瓣结构的支架。

与酵母对应物相比，NuA4L完全重新排列。TRRAP灵活地连接到NuA4L，这与它与酵母NuA的完全相反侧的牢固连接形成鲜明对比。活性测试支持的与SWR1L结合的模拟核小体表明，组蛋白交换机制的某些方面与酵母的例子不同。

此外，与SWR1中的移动肌动蛋白亚复合物相反，固定肌动蛋白模块、TRRAP的灵活性和核小体外DNA对交换活性的微弱影响导致了一种不同的、基于激活剂的TIP60-C与染色质结合的模式。

附：英文原文

Title: Structure of human TIP60-C histone exchange and acetyltransferase complex

Author: Li, Changqing, Smirnova, Ekaterina, Schnitzler, Charlotte, Crucifix, Corinne, Concordet, Jean Paul, Brion, Alice, Poterszman, Arnaud, Schultz, Patrick, Papai, Gabor, Ben-Shem, Adam

Issue&Volume: 2024-09-11

Abstract: Chromatin structure is a key regulator of DNA transcription, replication, and repair1. In humans, the TIP60/EP400 complex (TIP60-C) is a 20-subunit assembly that impacts chromatin structure via two enzymatic activities: ATP-dependent exchange of histone H2A/H2B for H2A.Z/H2B and histone acetylation, which in yeast are carried out by two independent complexes, SWR1 and NuA4, respectively2,3. How these activities are merged in humans into one super-complex and what this association entails for their structure, mechanism and recruitment to chromatin is unknown. Here we describe the 2.4-3.3 resolution structure of the endogenous human TIP60-C. We find a three lobed architecture composed of SWR1-like (SWR1L) and NuA4-like (NuA4L) parts, that associate with a TRRAP activator-binding module. The huge EP400 subunit harbors the ATPase motor, traverses twice the junction between SWR1L and NuA4L, and constitutes the scaffold of the three-lobed architecture. NuA4L is completely re-arranged compared to its yeast counterpart. TRRAP is flexibly tethered to NuA4L, in stark contrast to its robust connection to the complete opposite side of yeast NuA44-7. A modeled nucleosome bound to SWR1L, supported by activity tests, suggests that some aspects of the histone exchange mechanism diverge from the yeast example8,9. Furthermore, a fixed actin module, as opposed to the mobile actin subcomplex in SWR18, the flexibility of TRRAP and the weak effect of extra-nucleosomal DNA on exchange activity, lead to a different, activator-based, mode of enlisting TIP60-C to chromatin.

DOI: 10.1038/s41586-024-08011-w

Source: https://www.nature.com/articles/s41586-024-08011-w