PDF(Pubmed)
Abstract：
Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by IFIH1 in humans. Single nucleotide polymorphisms in the IFIH1 results in fatal genetic disorders such as Aicardi-Goutières syndrome and Singleton-Merten syndrome, and in increased risk of type I diabetes in humans. In this study, we chose four different amino acid substitutions of the MDA5 protein responsible for genetic disorders: MDA5L372F, MDA5A452T, MDA5R779H, and MDA5R822Q and analyzed their structural and functional relationships using molecular dynamic simulations. Our results suggest that the mutated complexes are relatively more stable than the wild-type MDA5. The radius of gyration, interaction energies, and intra-hydrogen bond analysis indicated the stability of mutated complexes over the wild type, especially MDA5L372F and MDA5R822Q. The dominant motions exhibited by the wild-type and mutant complexes varied significantly. Moreover, the betweenness centrality of the wild-type and mutant complexes showed shared residues for intra-signal propagation. The observed results indicate that the mutations lead to a gain of function, as reported in previous studies, due to increased interaction energies and stability between RNA and MDA5 in mutated complexes. These findings are expected to deepen our understanding of MDA5 variants and may assist in the development of relevant therapeutics against the disorders.
摘要：
黑色素瘤分化相关蛋白5(MDA5)是由IFIH1在人类中编码的关键RIG-I样受体RNA解旋酶。IFIH1中的单核苷酸多态性导致致命的遗传疾病，如Aicardi-Goutières综合征和Singleton-Merten综合征，以及人类患I型糖尿病的风险增加。在这项研究中,我们选择了MDA5蛋白的四个不同的氨基酸替换负责遗传性疾病：MDA5L372F，MDA5A452T,MDA5R779H,和MDA5R822Q，并使用分子动力学模拟分析了它们的结构和功能关系。我们的结果表明，突变的复合物比野生型MDA5相对更稳定。回转半径,相互作用能，和氢键内分析表明突变复合物相对于野生型的稳定性，特别是MDA5L372F和MDA5R822Q。野生型和突变体复合物表现出的显性运动差异很大。此外，野生型和突变体复合物的中间性中心性显示了信号内传播的共享残基。观察到的结果表明，突变导致功能的获得，正如以前的研究报告，由于突变复合物中RNA和MDA5之间的相互作用能和稳定性增加。这些发现有望加深我们对MDA5变体的理解，并可能有助于开发针对这些疾病的相关疗法。
