title: Solution structure of the Zbeta domain of human DNA-dependent activator of IFN-regulatory factors and its binding modes to B- and Z-DNAs.
abstract: The DNA-dependent activator of IFN-regulatory factors (DAI), also known as DLM-1/ZBP1, initiates an innate immune response by binding to foreign DNAs in the cytosol. For full activation of the immune response, three DNA binding domains at the N terminus are required: two Z-DNA binding domains (ZBDs), Zα and Zβ, and an adjacent putative B-DNA binding domain. The crystal structure of the Zβ domain of human DAI (hZβ(DAI)) in complex with Z-DNA revealed structural features distinct from other known Z-DNA binding proteins, and it was classified as a group II ZBD. To gain structural insights into the DNA binding mechanism of hZβ(DAI), the solution structure of the free hZβ(DAI) was solved, and its bindings to B- and Z-DNAs were analyzed by NMR spectroscopy. Compared to the Z-DNA-bound structure, the conformation of free hZβ(DAI) has notable alterations in the α3 recognition helix, the "wing," and Y145, which are critical in Z-DNA recognition. Unlike some other Zα domains, hZβ(DAI) appears to have conformational flexibility, and structural adaptation is required for Z-DNA binding. Chemical-shift perturbation experiments revealed that hZβ(DAI) also binds weakly to B-DNA via a different binding mode. The C-terminal domain of DAI is reported to undergo a conformational change on B-DNA binding; thus, it is possible that these changes are correlated. During the innate immune response, hZβ(DAI) is likely to play an active role in binding to DNAs in both B and Z conformations in the recognition of foreign DNAs.
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. kkim@med.skku.ac.kr
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Kim
authors.forename: Bulat I
authors.initials: BI
authors.lastname: Khayrutdinov
authors.forename: Chung-Kyung
authors.initials: CK
authors.lastname: Lee
authors.forename: Hae-Kap
authors.initials: HK
authors.lastname: Cheong
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Hyejin
authors.initials: H
authors.lastname: Park
authors.forename: Sangho
authors.initials: S
authors.lastname: Lee
authors.forename: Yang-Gyun
authors.initials: YG
authors.lastname: Kim
authors.forename: Jungoo
authors.initials: J
authors.lastname: Jee
authors.forename: Alexander
authors.initials: A
authors.lastname: Rich
authors.forename: Kyeong Kyu
authors.initials: KK
authors.lastname: Kim
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
mesh_terms: D043542:DNA, Z-Form / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins
chemical_list: D043542:DNA, Z-Form; D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; C485731:ZBP1 protein, human