Hicks Chad W, Gliech Colin R, Rahman Sanim, Zhang Xiangbin, Eneim Andrew S, Vasquez Stacy J, Holland Andrew J, Wolberger Cynthia
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Struct Mol Biol. 2025 Feb 20. doi: 10.1038/s41594-025-01502-y.
Phosphorylation of histone H3 threonine 3 (H3T3) by Haspin recruits the chromosomal passenger complex to the inner centromere and ensures proper cell cycle progression through mitosis. The mechanism by which Haspin binds to nucleosomes to phosphorylate H3T3 is not known. Here we report cryogenic electron microscopy structures of the human Haspin kinase domain bound to a nucleosome. In contrast with previous structures of histone-modifying enzymes, Haspin solely contacts the nucleosomal DNA, inserting into a supergroove formed by apposing major grooves of two DNA gyres. This binding mode provides a plausible mechanism by which Haspin can bind to nucleosomes in a condensed chromatin environment to phosphorylate H3T3. We identify key basic residues in the Haspin kinase domain that are essential for phosphorylation of nucleosomal histone H3 and binding to mitotic chromatin. Our structural data provide notable insight into a histone-modifying enzyme that binds to nucleosomes solely through DNA contacts.
Haspin对组蛋白H3苏氨酸3（H3T3）的磷酸化作用可将染色体乘客复合体招募至内着丝粒，并确保细胞周期通过有丝分裂正常进行。Haspin与核小体结合以磷酸化H3T3的机制尚不清楚。在此，我们报告了与核小体结合的人源Haspin激酶结构域的低温电子显微镜结构。与先前组蛋白修饰酶的结构不同，Haspin仅与核小体DNA接触，插入由两个DNA螺旋的相对大沟形成的超沟中。这种结合模式提供了一种合理的机制，通过该机制Haspin可以在浓缩染色质环境中与核小体结合以磷酸化H3T3。我们鉴定出Haspin激酶结构域中的关键碱性残基，这些残基对于核小体组蛋白H3的磷酸化以及与有丝分裂染色质的结合至关重要。我们的结构数据为一种仅通过DNA接触与核小体结合的组蛋白修饰酶提供了显著的见解。
