Lorton Benjamin M, Warren Christopher, Ilyas Humaira, Nandigrami Prithviraj, Hegde Subray, Cahill Sean, Lehman Stephanie M, Shabanowitz Jeffrey, Hunt Donald F, Fiser Andras, Cowburn David, Shechter David
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461.
Current address: Merck & Co., Inc., 2025 E Scott Ave., Rahway, NJ 07065.
bioRxiv. 2023 Sep 19:2023.09.18.558337. doi: 10.1101/2023.09.18.558337.
Histone chaperones-structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)-protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that, to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.
组蛋白伴侣是结构多样的非催化蛋白，富含酸性内在无序区域（IDR），可保护组蛋白免受不必要的核酸相互作用，并引导它们进出核小体。尽管它们具有保守性和普遍性，但伴侣酸性IDR的功能仍不清楚。在这里，我们表明Npm2和Nap1酸性IDR是TTLL4（微管蛋白酪氨酸连接酶样4）催化的翻译后谷氨酸-谷氨酰化的底物。我们证明，为了结合、稳定组蛋白并将其沉积到核小体中，伴侣酸性IDR起着DNA模拟物的作用。我们的生化、计算和生物物理研究表明，这些伴侣聚电解质酸性片段的谷氨酰化作用是增强DNA静电模拟，促进H2A/H2B异二聚体的结合和稳定，并促进核小体组装。这一发现为酸性IDR以前不清楚的功能以及翻译后修饰在染色质动力学中的调节作用提供了见解。
