Thermodynamic Model for B-Z Transition of DNA Induced by Z-DNA Binding Proteins

Abstract

Z-DNA is stabilized by various Z-DNA binding proteins (ZBPs) that play important roles in RNA editing, innate immune response, and viral infection. In this review, the structural and dynamics of various ZBPs complexed with Z-DNA are summarized to better understand the mechanisms by which ZBPs selectively recognize d(CG)-repeat DNA sequences in genomic DNA and efficiently convert them to left-handed Z-DNA to achieve their biological function. The intermolecular interaction of ZBPs with Z-DNA strands is mediated through a single continuous recognition surface which consists of an α3 helix and a β-hairpin. In the ZBP-Z-DNA complexes, three identical, conserved residues (N173, Y177, and W195 in the Zα domain of human ADAR1) play central roles in the interaction with Z-DNA. ZBPs convert a 6-base DNA pair to a Z-form helix via the B-Z transition mechanism in which the ZBP first binds to B-DNA and then shifts the equilibrium from B-DNA to Z-DNA, a conformation that is then selectively stabilized by the additional binding of a second ZBP molecule. During B-Z transition, ZBPs selectively recognize the alternating d(CG)_n sequence and convert it to a Z-form helix in long genomic DNA through multiple sequence discrimination steps. In addition, the intermediate complex formed by ZBPs and B-DNA, which is modulated by varying conditions, determines the degree of B-Z transition.

Keywords: B-Z transition; DNA-protein interaction; Z-DNA; Z-DNA binding protein.

Figure 1

(a) Multiple sequence alignment of ZBPs: hZα_ADAR1, hZβ_ADAR1, human ADAR1; mZα_ADAR1, mZβ_ADAR1, murine ADAR1; hZα_DAI, hZβ_DAI, human DAI; mZα_DAI, mZβ_DAI, murine DAI; yabZα_E3L, Yaba-like disease virus E3L; vZα_E3L, vaccinia virus E3L; orfZα_E3L, orf virus E3L; lsZα_E3L, lumpy skin disease virus E3L; spZα_E3L, swinepox virus E3L; caZα_PKZ, caZβ_PKZ, goldfish PKZ; drZα_PKZ, drZβ_PKZ, zebrafish PKZ. Numbering and secondary structural elements for hZα_ADAR1 and hZβ_ADAR1 are shown above the sequence. Yellow and gray bars indicate residues important for Z-DNA recognition and protein folding, respectively. (b) Overview of the hZα_ADAR1 domain bound to left-handed Z-DNA (PDB id: 1QBJ) [7]. (c) View of the DNA recognition surface of hZα_ADAR1 (PDB id: 1QBJ) [7]. The green lines indicate the H-bonding interactions. In (b,c), the backbone structure of hZα_ADAR1 domain and Z-DNA duplex, d(TCGCGCG)₂, are represented by the green ribbon and element-based stick presentation, respectively.

Figure 2

Protein residues involved Z-DNA/Z-RNA interactions in (a) hZα_ADAR1–dT(CG)₃ [7], (b) mZα_DLM1–dT(CG)₃ [29], (c) yabZα_E3L–dT(CG)₃ [30], (d) caZα_PKZ–dT(CG)₃ [31], (e) hZβ_DAI–dT(CG)₃ [32], and (f) hZα_ADAR1–rU(CG)₃ complexes [33]. Intermolecular H-bonds and van der Waals contacts are indicated by solid lines and open circles, respectively. The water molecules in key positions within the protein–DNA interface are indicated by ovals.

Figure 3

(a) Mechanism for the B-Z conformational transition of a 6-bpDNA by two ZBPs [41]. (b) Relative Z-DNA populations (f_Z) of d(CGCGCG)2 (grey circle) [41], d(CACGTG)₂ (dark green circle) [42], and d(CGTACG)₂ (brown circle) [42] induced by hZα_ADAR1 in NMR buffer (pH = 8.0) containing 100 mM NaCl as a function of [P]_t/[N]_t ratio. (c) f_Z of d(CGCGCG)₂ induced by hZα_ADAR1 (grey circle) [41], yabZα_E3L (orange triangle) [43], and hZβ_DAI (purple triangle) [44] in NMR buffer (pH = 8.0) containing 100 mM NaCl as a function of [P]_t/[N]_t ratio. (d) f_Z of d(CGCGCG)₂ at 10 mM NaCl (blue square) and d(TCGCGCG)₂ at 10 mM (red square), 100 mM (pink square), and 250 mM NaCl (light pink square) induced by caZα_PKZ [45].