Biochemical characterization and preliminary X-ray crystallographic study of the domains of human ZBP1 bound to left-handed Z-DNA

Ha, Soonhoi; Quyền, Đồng Văn; Hwang, Hye‐Yeon; Oh, Doo-Byoung; Brown, Billyde; Lee, Seon Min; Park, Hyun-Ju; Ahn, Jin-Hyun; Kim, Kyeong Kyu; Kim, Yang‐Gyun

doi:10.1016/j.bbapap.2005.12.012

Cited by 29 publications

(24 citation statements)

References 20 publications

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“…hZ␤ DAI does not have residues that play a role equivalent to Pro or Thr in the wing region (Fig. 1), but it still has nearly the same Z-DNA-converting activity as hZ␣ ADAR1 (6,14). Therefore, it was anticipated that there would be another residue in the wing region that must bind to Z-DNA.…”

Section: Resultsmentioning

confidence: 99%

“…From structural and biochemical studies on the first ZBD of DAI (6,9,14,19), it was expected that hZ␣ DAI shared a canonical ZBD fold and a similar binding mode with other members of what we call group I ZBDs. This study reveals that hZ␤ DAI belongs to what we call group II ZBDs and has a distinct Z-DNA binding mode.…”

Section: The Alternative Binding Mode Is Supported By Z-dna Convertingmentioning

confidence: 99%

“…It has already been established that each of the 2 ZBDs of DAI individually possesses Z-DNA converting activity and can bind to Z-DNA independently (6,14,19). To investigate their joint binding modes, Z-DNA converting activities were measured for hZ␣␤ DAI, hZ␣␤ DAI Y50A, and Z␣␤ DAI Y145A (Fig.…”

Section: The Alternative Binding Mode Is Supported By Z-dna Convertingmentioning

confidence: 99%

“…The first DNA binding domain of DAI (Z␣ DAI, also known as Z␣ DLM-1 or Z␣ ZBP1 ) was well characterized as a canonical ZBD in structural and biochemical studies (9). The second ZBD (Z␤ DAI ) was also shown to bind Z-DNA based on its binding specificity for Z-DNA and its ability to convert B-DNA to Z-DNA, as measured in the CD spectrum (6,14). However, some residues that are known to mediate ZBD/ DNA interactions in other systems are not present in hZ␤ DAI , suggesting that the binding mode of Z␤ DAI with DNA might be different from that of other canonical ZBDs (Fig.…”

mentioning

confidence: 99%

“…1). They all bind tightly and specifically to Z-DNA and usually are able to convert B-DNA to Z-DNA (8)(9)(10)(11)(12)(13)(14). Structural studies of ZBDs have shown that they all share an ␣/␤ architecture consisting of 3 ␤-strands and 3 ␣-helices (9,(15)(16)(17).…”

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confidence: 99%

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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

Kim

Hwang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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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 (hZ␤DAI) shows significant variation in the sequence of the residues that are essential for DNA binding. In this article, the crystal structure of the hZ␤DAI/Z-DNA complex reveals that hZ␤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 ␤-strand rather than residues in the ␤-loop contributes to DNA binding, and part of the (␣3) 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. circular dichroism ͉ hydrogen bonding ͉ interferon induction ͉ X-ray crystallography ͉ innate immunity T he innate immune response is essential for protection from foreign invasion, acting as an immediate cellular defense mechanism. Nucleic acids are known as one of the triggers for activation of the innate immune response (1-3). Recent reports have indicated the presence of a new cytosolic DNA sensor that can initiate an innate immune response independent of the endosomic Toll-like receptor 9 (4, 5). Z-DNA binding protein 1 (ZBP1), also known as DLM-1, was identified as the first innate immune activator that senses cytosolic DNAs (4). In response to foreign DNA, this protein activates type I IFN and other immune responses and was therefore named DAI (DNA-dependent activator of IFN-regulatory factors; ref 4). DAI contains 2 tandem Z-DNA binding domains (ZBDs or Z␣ and Z␤) at its N terminus and a third DNA binding region (D3) located next to the second ZBD. D3 is a novel domain and is reported to bind right-handed B-DNA (4). Upon activation, the C terminus of DAI binds to Tank binding kinase 1 (TBK1), a serine/threonine kinase, and to IFN regulatory factor 3 (IRF3), a transcription factor (4). The N-terminal region, including D3, is thought to be essential for sensing DNA, as shown by its ability to bind to Z-DNA and synthetic B-DNA (4). For the full activation of an in vivo DNA-dependent immune response, all 3 DNA-binding regions are required (5). At the molecular level, it has been suggested that dimerization of DAI results in activation of the innate immune response (5). At the cellular level, it is known that the localization of DAI and its association with stress granules is regulated by ZBDs (6,7).ZBDs that are found in DAI are also found in the editing enzyme dsRNA adenosine deaminase (ADAR1) in vertebrates and in fish PKZ protein kinase containing Z-DNA-binding domains and in the E3L of pox viruses (Fig. 1). They ...

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Section: Resultsmentioning

confidence: 99%

Section: The Alternative Binding Mode Is Supported By Z-dna Convertingmentioning

confidence: 99%

Section: The Alternative Binding Mode Is Supported By Z-dna Convertingmentioning

confidence: 99%

mentioning

confidence: 99%