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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

Sung Chul Ha, Doyoun Kim, Hye-Yeon Hwang, Alexander Rich, Yang-Gyun Kim and Kyeong Kyu Kim
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 52 (Dec. 30, 2008), pp. 20671-20676
Stable URL: http://www.jstor.org/stable/25464966
Page Count: 6
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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 $({\rm hZ}\beta _{{\rm DAI}})$ shows significant variation in the sequence of the residues that are essential for DNA binding. In this article, the crystal structure of the ${\rm hZ}\beta _{{\rm DAI}}/{\rm Z}\text{-}{\rm DNA}$ complex reveals that ${\rm hZ}\beta _{{\rm DAI}}$ 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.

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