Structure and Mechanism of Hexameric Helicases

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Abstract
Hexameric helicases are responsible for many biological processes, ranging from DNA replication in various life domains to DNA repair, transcriptional regulation and RNA metabolism, and encompass superfamilies 3–6 (SF3–6). To harness the chemical energy from ATP hydrolysis for mechanical work, hexameric helicases have a conserved core engine, called ASCE, that belongs to a subdivision of the P-loop NTPases. Some of the ring helicases (SF4 and SF5) use a variant of ASCE known as RecA-like, while some (SF3 and SF6) use another variant known as AAA+ fold. The NTP-binding sites are located at the interface between monomers and include amino-acid residues coming from neighbouring subunits, providing a mean for small structural changes within the ATP-binding site to be amplified into large inter-subunit movement. The ring structure has a central channel which encircles the nucleic acid. The topological link between the protein and the nucleic acid substrate increases the stability and processivity of the enzyme. This is probably the reason why within cellular systems the critical step of unwinding dsDNA ahead of the replication fork seems to be almost invariably carried out by a toroidal helicase, whether in bacteria, archaea or eukaryotes, as well as in some viruses. Over the last few years, a large number of biochemical, biophysical and structural data have thrown new light onto the architecture and function of these remarkable machines. Although the evidence is still limited to a couple of systems, biochemical and structural results suggest that motors based on RecA and AAA+ folds have converged on similar mechanisms to couple ATP-driven conformational changes to movement along nucleic acids.

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