疾病相关突变通过动态变构效应和溶剂暴露影响DNA甲基转移酶1的功能

文献信息

中文摘要

DNA甲基转移酶1（DNMT1）酶的突变可导致神经退行性疾病，包括常染色体显性小脑性共济失调-耳聋和神经病（ADCA-DN）以及遗传性感觉和自主神经病1E型（HSAN1E）。这些突变对DNMT1结构动力学的影响在很大程度上仍不清楚。在此，我们对野生型（WT）DNMT1及其与ADCA-DN相关的突变体（A554V、G589A和V590F）以及与HSAN1E相关的突变体（D490E-P491Y和Y495C）进行了广泛的分子动力学研究。第一组突变体相对于WT DNMT1增加了结构灵活性并破坏了变构通讯。这些发现为在这些突变体中观察到的体外热稳定性降低提供了分子解释。第二组对结构灵活性和变构通讯有类似影响，并增加了突变位点的溶剂暴露，为实验观察到的异常蛋白质降解和切割提供了合理的结构解释。此外，所有研究的变异体都改变了酶最显著的大规模运动。这种运动的破坏，加上结构稳定性的降低，可能影响DNMT1与其细胞伙伴的分子识别过程。总体而言，这项研究揭示了ADCA-DN和HSAN1E的分子机制，可为治疗方法的开发提供信息。

英文摘要

Mutations in the DNA methyltransferase 1 (DNMT1) enzyme can lead to neurodegenerative diseases, including autosomal dominant cerebellar ataxia-deafness and neuropathy (ADCA-DN) and hereditary sensory and autonomic neuropathy type 1E (HSAN1E). The impact of these mutations on the structural dynamics of DNMT1 remains largely unknown. Here, we present an extensive molecular dynamics investigation of wild-type (WT) DNMT1 and its mutants associated with ADCA-DN (A554V, G589A, and V590F) and HSAN1E (D490E-P491Y and Y495C). The first group of mutants increases structural flexibility and disrupts the allosteric communication relative to WT DNMT1. These findings provide a molecular explanation for the reduced in vitro thermostability observed in these mutants. The second group has a similar impact on structural flexibility and allosteric communication and increases solvent exposure at mutant sites, offering a plausible structural explanation for the experimentally observed aberrant protein degradation and cleavage. Furthermore, all the investigated variants alter the most significant large-scale motions of the enzyme. This disruption of motion, together with decreased structural stability, may affect DNMT1's molecular recognition processes with its cellular partners. Overall, this study sheds light on the molecular mechanisms underlying ADCA-DN and HSAN1E, which could inform the development of therapies.