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The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA reveals an unusual binding mode to Z-DNA
Authors:Sung Chul Ha   Doyoun Kim   Hye-Yeon Hwang   Alexander Rich   Yang-Gyun Kim     Kyeong Kyu Kim
Affiliation:aDepartment of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea; ;bDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and ;cDepartment of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
Abstract:Mammalian DAI (DNA-dependent activator of IFN-regulatory factors), an activator of the innate immune response, senses cytosolic DNA by using 2 N-terminal Z-DNA binding domains (ZBDs) and a third putative DNA binding domain located next to the second ZBD. Compared with other previously known ZBDs, the second ZBD of human DAI (hZβDAI) shows significant variation in the sequence of the residues that are essential for DNA binding. In this article, the crystal structure of the hZβDAI/Z-DNA complex reveals that hZβDAI has a similar fold to that of other ZBDs, but adopts an unusual binding mode for recognition of Z-DNA. A residue in the first β-strand rather than residues in the β-loop contributes to DNA binding, and part of the (α3) recognition helix adopts a 310 helix conformation. The role of each residue that makes contact with DNA was confirmed by mutational analysis. The 2 ZBDs of DAI can together bind to DNA and both are necessary for full B-to-Z conversion. It is possible that binding 2 DAIs to 1 dsDNA brings about dimerization of DAI that might facilitate DNA-mediated innate immune activation.
Keywords:circular dichroism   hydrogen bonding   interferon induction   X-ray crystallography   innate immunity
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