Structural and Energetic Details for the Formation of cGAS-DNA Oligomers
Li, X.; Li, W.
Show abstract
Upon binding to cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) is activated to catalyze the synthesis of cGAMP, which then activates downstream effectors and induces innate immune responses. The activation of cGAS relies on the formation of cGAS-DNA oligomers and liquid phase condensation, which are sensitive to the length and concentration of DNA. For a thorough understanding of such a length-and concentration-dependent activation, the details of the cGAS-DNA oligomerization are required. Here, with molecular dynamics (MD) simulations, we report the structure of the cGAS-DNA monomer (the cGAS1-DNA1 complex), in which the DNA binds simultaneously to the major parts of two DNA-binding sites as observed in the cGAS-DNA dimer (the cGAS2-DNA2 complex) and the active site is largely immature. Energetic analysis reveals that two cGAS1-DNA1 complexes are just slightly less stable than the cGAS2-DNA2 complex and the energy barrier for the formation of cGAS2-DNA2 complex from two cGAS1-DNA1 complexes is high, suggesting that cGAS-DNA oligomerization is unfavored thermodynamically and kinetically in low concentration of cGAS and DNA. However, the formation of cGAS4-DNA2 complex from one molecule of cGAS2-DNA2 complex between cGAS and long DNA and two molecules of cGAS are energetically favored without energy barrier.
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