Yu Jiali, Sui Fengrui, Gu Feng, Li Wanjun, Yu Zishuo, Wang Qianmin, He Shuang, Wang Li, Xu Yanhui
Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, New Cornerstone Science Laboratory, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai, China.
The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology of China, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
Cell Discov. 2024 Feb 8;10(1):15. doi: 10.1038/s41421-023-00640-1.
Histone variant H2A.Z is found at promoters and regulates transcription. The ATP-dependent chromatin remodeler SRCAP complex (SRCAP-C) promotes the replacement of canonical histone H2A-H2B dimer with H2A.Z-H2B dimer. Here, we determined structures of human SRCAP-C bound to H2A-containing nucleosome at near-atomic resolution. The SRCAP subunit integrates a 6-subunit actin-related protein (ARP) module and an ATPase-containing motor module. The ATPase-associated ARP module encircles half of the nucleosome along the DNA and may restrain net DNA translocation, a unique feature of SRCAP-C. The motor module adopts distinct nucleosome binding modes in the apo (nucleotide-free), ADP-bound, and ADP-BeF-bound states, suggesting that ATPase-driven movement destabilizes H2A-H2B by unwrapping the entry DNA and pulls H2A-H2B out of nucleosome through the ZNHIT1 subunit. Structure-guided chromatin immunoprecipitation sequencing analysis confirmed the requirement of H2A-contacting ZNHIT1 in maintaining H2A.Z occupancy on the genome. Our study provides structural insights into the mechanism of H2A-H2A.Z exchange mediated by SRCAP-C.
组蛋白变体H2A.Z存在于启动子区域并调控转录。ATP依赖的染色质重塑因子SRCAP复合物（SRCAP-C）促进用H2A.Z-H2B二聚体替换经典组蛋白H2A-H2B二聚体。在此，我们以近原子分辨率确定了与含H2A的核小体结合的人源SRCAP-C的结构。SRCAP亚基整合了一个6亚基的肌动蛋白相关蛋白（ARP）模块和一个含ATP酶的马达模块。与ATP酶相关的ARP模块沿着DNA环绕核小体的一半，可能会抑制净DNA易位，这是SRCAP-C的一个独特特征。马达模块在无核苷酸（apo）、结合ADP和结合ADP-BeF的状态下采用不同的核小体结合模式，表明ATP酶驱动的运动通过解开进入DNA使H2A-H2B不稳定，并通过ZNHIT1亚基将H2A-H2B从核小体中拉出。基于结构的染色质免疫沉淀测序分析证实了与H2A接触的ZNHIT1在维持基因组上H2A.Z占据率方面的必要性。我们的研究为SRCAP-C介导的H2A-H2A.Z交换机制提供了结构上的见解。
