Institute for Advanced Study, Shenzhen University, Room 341, Administration Building, Shenzhen 518060, China.
Phys Chem Chem Phys. 2020 Nov 25;22(45):26390-26401. doi: 10.1039/d0cp04162a.
Cyclic GMP-AMP synthase (cGAS) can detect the presence of cytoplasmic DNA and activate the innate immune system via the cGAS-STING pathway. Although several structures of cGAS-DNA complexes were resolved recently, the molecular mechanism of cGAS in its recognition of DNA has not yet been fully understood. In order to reveal the subtle differences between human and mouse cGAS in terms of their DNA-binding mechanisms, four systems, both human and mouse cGAS in complex with two different DNA sequences of equal length, were studied by molecular dynamics simulations and molecular mechanics/generalized Born surface area analysis. Several residues, including ARG176/ARG161, ARG195/ARG180, ASN210/ASN196, LYS384/LYS372, CYM397/CYM385, LYS403/LYS391, LYS407/LYS395, and LYS411/LYS399, were identified to be the common key residues in the recognition of DNA for cGAS in both humans and mice. In addition, four residue pairs LYS173/ARG158, ASP177/LYS162, CYS199/LYS184, and GLU398/SER387 were suggested to be the major residues that make human cGAS and mouse cGAS different in terms of their binding to DNA. Besides the well-known zinc-thumb domain, two residues at the kink of the spine helix were also proposed for the first time to be the major binding motifs in cGAS-DNA interaction.
环鸟苷酸-腺苷酸合酶（cGAS）可以检测细胞质 DNA 的存在，并通过 cGAS-STING 途径激活先天免疫系统。尽管最近已经解析了几个 cGAS-DNA 复合物的结构，但 cGAS 识别 DNA 的分子机制尚未完全理解。为了揭示人类和小鼠 cGAS 在 DNA 结合机制方面的细微差异，通过分子动力学模拟和分子力学/广义 Born 表面面积分析研究了四个系统，即与人 cGAS 和鼠 cGAS 分别与两个长度相等的不同 DNA 序列形成的复合物。确定了几个残基，包括 ARG176/ARG161、ARG195/ARG180、ASN210/ASN196、LYS384/LYS372、CYM397/CYM385、LYS403/LYS391、LYS407/LYS395 和 LYS411/LYS399，是人类和小鼠 cGAS 识别 DNA 的共同关键残基。此外，提出了四个残基对 LYS173/ARG158、ASP177/LYS162、CYS199/LYS184 和 GLU398/SER387，认为它们是人类 cGAS 和鼠 cGAS 在与 DNA 结合方面不同的主要残基。除了众所周知的锌指结构域外，首次提出螺旋突环处的两个残基也是 cGAS-DNA 相互作用的主要结合基序。
