Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany; The Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology, Heidelberg University, Heidelberg, Germany.
Computational Structural Biology Laboratory, Department of Cellular and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany; Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Münster, Germany.
Biophys J. 2018 May 22;114(10):2363-2375. doi: 10.1016/j.bpj.2018.04.034. Epub 2018 May 11.
Linker histone (LH) proteins play a key role in higher-order structuring of chromatin for the packing of DNA in eukaryotic cells and in the regulation of genomic function. The common fruit fly (Drosophila melanogaster) has a single somatic isoform of the LH (H1). It is thus a useful model organism for investigating the effects of the LH on nucleosome compaction and the structure of the chromatosome, the complex formed by binding of an LH to a nucleosome. The structural and mechanistic details of how LH proteins bind to nucleosomes are debated. Here, we apply Brownian dynamics simulations to compare the nucleosome binding of the globular domain of D. melanogaster H1 (gH1) and the corresponding chicken (Gallus gallus) LH isoform, gH5, to identify residues in the LH that critically affect the structure of the chromatosome. Moreover, we investigate the effects of posttranslational modifications on the gH1 binding mode. We find that certain single-point mutations and posttranslational modifications of the LH proteins can significantly affect chromatosome structure. These findings indicate that even subtle differences in LH sequence can significantly shift the chromatosome structural ensemble and thus have implications for chromatin structure and transcriptional regulation.
连接组蛋白 (LH) 蛋白在真核细胞中 DNA 的包装和基因组功能的调节中对染色质的高级结构起着关键作用。常见的黑腹果蝇 (Drosophila melanogaster) 只有一种体细胞 LH 同工型 (H1)。因此，它是研究 LH 对核小体紧缩和染色质体结构（LH 与核小体结合形成的复合物）影响的有用模型生物。LH 蛋白与核小体结合的结构和机制细节存在争议。在这里，我们应用布朗动力学模拟来比较黑腹果蝇 H1 的球状结构域 (gH1) 和相应的鸡 (Gallus gallus) LH 同工型 gH5 与核小体的结合，以确定对染色质体结构有重要影响的 LH 中的残基。此外，我们还研究了翻译后修饰对 gH1 结合模式的影响。我们发现，LH 蛋白的某些单点突变和翻译后修饰可以显著影响染色质体结构。这些发现表明，LH 序列的微小差异甚至可以显著改变染色质体结构组合，从而对染色质结构和转录调控产生影响。
