Park Giho, Patel Avinash B, Wu Carl, Louder Robert K
Biochemistry, Cellular and Molecular Graduate Program, Johns Hopkins School of Medicine; Baltimore, MD 21205, USA.
Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine; Baltimore, MD 21205, USA.
bioRxiv. 2024 Jul 30:2024.07.30.605802. doi: 10.1101/2024.07.30.605802.
H2A.Z is a conserved histone variant that is localized to specific genomic regions where it plays important roles in transcription, DNA repair, and replication. Central to the biochemistry of human H2A.Z are the SRCAP and TIP60 chromatin remodelers, homologs of yeast SWR1 which catalyzes ATP-dependent H2A.Z exchange. Here, we use cryo-electron microscopy to resolve six structural states of the native SRCAP complex, uncovering conformational intermediates interpreted as a stepwise path to full nucleosome engagement. We also resolve the structure of the native TIP60 complex which consists of a structured core from which flexibly tethered chromatin binding domains emerge. Despite the shared subunit composition, the core of TIP60 displays divergent architectures from SRCAP that structurally disfavor nucleosome engagement, suggesting a distinct biochemical function.
H2A.Z是一种保守的组蛋白变体，定位于特定的基因组区域，在转录、DNA修复和复制中发挥重要作用。人类H2A.Z生物化学的核心是SRCAP和TIP60染色质重塑因子，它们是酵母SWR1的同源物，催化ATP依赖性H2A.Z交换。在这里，我们使用冷冻电子显微镜解析了天然SRCAP复合物的六种结构状态，揭示了构象中间体，这些中间体被解释为通向完全核小体结合的逐步路径。我们还解析了天然TIP60复合物的结构，它由一个结构化核心组成，从中出现灵活连接的染色质结合结构域。尽管亚基组成相同，但TIP60的核心显示出与SRCAP不同的结构，在结构上不利于核小体结合，这表明其具有独特的生化功能。
