Key Laboratory of Molecular Design for Plant Cell Factory of Guangdong Higher Education Institutes, Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
Novo Nordisk Center for Protein Research (CPR), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Nucleic Acids Res. 2022 May 20;50(9):5349-5368. doi: 10.1093/nar/gkac303.
Histone chaperones regulate all aspects of histone metabolism. NASP is a major histone chaperone for H3-H4 dimers critical for preventing histone degradation. Here, we identify two distinct histone binding modes of NASP and reveal how they cooperate to ensure histone H3-H4 supply. We determine the structures of a sNASP dimer, a complex of a sNASP dimer with two H3 α3 peptides, and the sNASP-H3-H4-ASF1b co-chaperone complex. This captures distinct functionalities of NASP and identifies two distinct binding modes involving the H3 α3 helix and the H3 αN region, respectively. Functional studies demonstrate the H3 αN-interaction represents the major binding mode of NASP in cells and shielding of the H3 αN region by NASP is essential in maintaining the H3-H4 histone soluble pool. In conclusion, our studies uncover the molecular basis of NASP as a major H3-H4 chaperone in guarding histone homeostasis.
组蛋白伴侣调节组蛋白代谢的各个方面。NASP 是 H3-H4 二聚体的主要组蛋白伴侣，对于防止组蛋白降解至关重要。在这里，我们确定了 NASP 的两种不同的组蛋白结合模式，并揭示了它们如何合作以确保组蛋白 H3-H4 的供应。我们确定了 sNASP 二聚体、sNASP 二聚体与两个 H3α3 肽的复合物以及 sNASP-H3-H4-ASF1b 共伴侣复合物的结构。这捕获了 NASP 的不同功能，并分别确定了涉及 H3α3 螺旋和 H3αN 区域的两种不同的结合模式。功能研究表明，H3αN 相互作用代表了 NASP 在细胞中的主要结合模式，并且 NASP 对 H3αN 区域的屏蔽对于维持 H3-H4 组蛋白可溶性池至关重要。总之，我们的研究揭示了 NASP 作为主要的 H3-H4 伴侣在保护组蛋白动态平衡方面的分子基础。
