Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Department of Biochemistry, Science Institute, University of Iceland, Reykjavík, Iceland.
Nat Chem. 2022 Feb;14(2):224-231. doi: 10.1038/s41557-021-00839-3. Epub 2022 Jan 6.
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.
带高电荷的无序蛋白是染色质结构和转录活性的重要调节剂。在这里，我们发现了一种依赖于这些多电荷聚合物及其复合物中显著的动态无序的惊人分子竞争机制。高度带正电荷的人类连接组蛋白 H1.0（H1）与核小体具有超高亲和力结合，这意味着停留时间与有效的生物调节不兼容。然而，我们表明，当与核小体结合时，H1 的无序区域保留其大振幅动力学，这使得高度带负电荷和无序的组蛋白伴侣原胸腺素α能够有效地侵入 H1-核小体复合物，并通过竞争取代机制置换 H1，大大加速 H1 的解离。通过整合实验和模拟，我们建立了一个分子模型，从结构和动力学上合理地解释了这个过程的显著动力学。鉴于核蛋白组中多聚电解质序列的丰富性，这种机制很可能在细胞调节中广泛存在。
