瑞士苏黎世大学Schuler, Benjamin团队报道了聚电解质与无序蛋白竞争驱动核小体中连接组蛋白的释放。相关研究成果于2022年1月6日发表在国际顶尖学术期刊《自然—化学》。

高电荷内在无序蛋白质是染色质结构和转录活性的重要调节因子。

该文中，研究人员发现了一种令人惊讶的分子竞争机制，它依赖于这些聚电解质及其复合物中存在的明显的动力学无序。高正电荷的人类连接蛋白组蛋白H1.0（H1）以超高亲和力结合核小体，这意味着停留时间与有效的生物调节不相容。然而，研究人员发现H1的无序区域在与核小体结合时仍保持其大振幅动力学，这使得高度负电荷和无序的组蛋白伴侣原胸腺素α能够有效侵入H1-核小体复合物，并通过竞争替代机制置换H1，大大加速了H1解离。

通过实验和模拟综合研究，研究人员建立了一个分子模型，从结构和动力学上揭示了这一过程的显著动力学。鉴于核蛋白质组中有丰富的聚电解质序列，该机制可能在细胞调节中广泛存在。

附：英文原文

Title: Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein

Author: Heidarsson, Ptur O., Mercadante, Davide, Sottini, Andrea, Nettels, Daniel, Borgia, Madeleine B., Borgia, Alessandro, Kilic, Sinan, Fierz, Beat, Best, Robert B., Schuler, Benjamin

Issue&Volume: 2022-01-06

Abstract: Highly charged intrinsically disordered proteins are essential regulators of chromatin structure and transcriptional activity. Here we identify a surprising mechanism of molecular competition that relies on the pronounced dynamical disorder present in these polyelectrolytes and their complexes. The highly positively charged human linker histone H1.0 (H1) binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. However, we show that the disordered regions of H1 retain their large-amplitude dynamics when bound to the nucleosome, which enables the highly negatively charged and disordered histone chaperone prothymosin α to efficiently invade the H1–nucleosome complex and displace H1 via a competitive substitution mechanism, vastly accelerating H1 dissociation. By integrating experiments and simulations, we establish a molecular model that rationalizes the remarkable kinetics of this process structurally and dynamically. Given the abundance of polyelectrolyte sequences in the nuclear proteome, this mechanism is likely to be widespread in cellular regulation.

DOI: 10.1038/s41557-021-00839-3

Source: https://www.nature.com/articles/s41557-021-00839-3