Abstract
Type IIA DNA topoisomerases (TopoIIAs) are essential and ubiquitous enzymes that catalyze ATP-dependent passage of one DNA duplex (T-segment) through a transient double-stranded breakage in another (G-segment). Such an activity alters DNA topology, allowing these enzymes to solve topological conflicts arising during cellular DNA transactions. Most bacteria harbor two closely related yet functionally distinct TopoIIAs namely DNA gyrase and TopoIV. DNA gyrase supports replication and transcription with its unique supercoiling activity, whereas TopoIV preferentially relaxes (＋) supercoils and is the main decatenating enzyme required for chromosome segregation. Mounting biochemical evidences suggest that the specialized activities of DNA gyrase and Topo IV depend on their respective C-terminal domains (CTDs). However, the underlying structural mechanism remains enigmatic. Using X-ray crystallography, we have determined crystal structures of TopoIV CTD from B. stearothermophilus (BsParC-CTD) as well as the DNA gyrase CTDs from Escherichia coli (EcGyrA-CTD) and Xanthomonas campestris (XcGyrA-CTD). All of them adopt a β-propeller-like fold termed β-pinwheel. Through structural and biochemical analyses, several unique structural features of these domains have been recognized and tested for the functional relevance. In particular, we have identified a highly conserved β-strand-bearing proline located in GyrA-CTD which is crucial for gyrase to exhibit efficient (－) supercoiling activity. This proline introduces structural-twist in GyrA-CTD, which results in spatial lift of the basic GyrA-box motif and an overall non-planar DNA-binding surface suitable for unidirectional DNA wrapping. In contrast, due to the lack of GyrA-box motif, the DNA-binding surface of ParC-CTD is relatively flat. This structural difference may represent a key determinant for the functional distinction between the two bacterial TopoIIAs
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