Sahoo Sthitaprajna, Son Seungwoo, Lee Hak-Kyo, Lee Jun-Yeong, Gosu Vijayakumar, Shin Donghyun
Department of Agricultural Convergence Technology, Jeonbuk National University, Jeonju, Republic of Korea.
Department of Animal Biotechnology, Jeonbuk National University, Jeonju, Republic of Korea.
J Biomol Struct Dyn. 2024 Mar;42(5):2603-2615. doi: 10.1080/07391102.2023.2206907. Epub 2023 May 3.
AIM2 and IFI16 are the most studied members of AIM2-like receptors (ALRs) in humans and share a common N-Terminal PYD domain and C-terminal HIN domain. The HIN domain binds to dsDNA in response to the invasion of bacterial and viral DNA, and the PYD domain directs apoptosis-associated speck-like protein protein-protein interactions. Hence, activation of AIM2 and IFI16 is crucial for protection against pathogenic assaults, and any genetic variation in these inflammasomes can dysregulate the human immune system. In this study, different computational tools were used to identify the most deleterious and disease-causing non-synonymous single nucleotide polymorphisms (nsSNPs) in AIM2 and IFI16 proteins. Molecular dynamic simulation was performed for the top damaging nsSNPs to study single amino acid substitution-induced structural alterations in AIM2 and IFI16. The observed results suggest that the variants G13V, C304R, G266R, and G266D for AIM2, and G13E and C356F are deleterious and affect structural integrity. We hope that the suggested deleterious nsSNPs and structural dynamics of AIM2 and IFI16 variants will guide future research to better understand the function of these variants with large-scale studies and may assist in fresher therapeutics focusing on these polymorphisms.Communicated by Ramaswamy H. Sarma.
AIM2和IFI16是人类中研究最多的AIM2样受体（ALR）成员，它们共享一个共同的N端PYD结构域和C端HIN结构域。HIN结构域在细菌和病毒DNA入侵时与双链DNA结合，而PYD结构域指导凋亡相关斑点样蛋白的蛋白质-蛋白质相互作用。因此，AIM2和IFI16的激活对于抵御病原体攻击至关重要，这些炎性小体中的任何基因变异都可能使人类免疫系统失调。在本研究中, 使用了不同的计算工具来识别AIM2和IFI16蛋白中最有害和致病的非同义单核苷酸多态性（nsSNP）。对最具破坏性的nsSNP进行了分子动力学模拟，以研究单个氨基酸取代引起的AIM2和IFI16结构改变。观察结果表明，AIM2的G13V、C304R、G266R和G266D变体以及G13E和C356F变体是有害的，并影响结构完整性。我们希望所提出的有害nsSNP以及AIM2和IFI16变体的结构动力学将指导未来的研究，以便通过大规模研究更好地理解这些变体的功能，并可能有助于针对这些多态性的更新颖的治疗方法。由Ramaswamy H. Sarma传达。
