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.
Highlights
Left-handed Z-DNA is a higher energy conformation than right-handed B-DNA
An NMR study found that free hZβDAI has notable alterations in the α3 helix, the β-hairpin, and Y145 which are critical in Z-DNA recognition [38]
These results indicate that, unlike some other Zα domains, structural flexibility of hZβDAI is required for Z-DNA binding [38]
Summary
Left-handed Z-DNA is a higher energy conformation than right-handed B-DNA. Z-DNA was first found in a polymer of alternating d(CG)n DNA duplexes observed in high salt conditions [1]; its crystal structure was reported in 1979 [2]. A distinct biological function of Z-DNA is suggested by the discovery of various Z-DNA binding proteins (ZBPs). ADAR1 has two left-handed Z-DNA binding domains (ZBDs), Zα and Zβ, at its NH2 -terminus [7,9]. A functional analogue of PKR, PKZ contains two ZBDs in the cytosol [20,21,22]. A functional analogue of PKR, PKZ contains two ZBDs instead instead of dsRNA binding domains [23,24,25,26]. Similar to PKR, the phosphorylation function of PKZ is of dsRNA binding domains [23,24,25,26]. Residuesimportant importantfor forZ-DNA recognition and ADAR1 domain bound to left-handed protein folding, respectively.
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