Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate

Ferdos Abid Ali, Ludovic Renault, Julian Gannon, Hailey L. Gahlon, Abhay Kotecha, Jin Chuan Zhou, David Rueda and Alessandro Costa ()
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Ferdos Abid Ali: Macromolecular Machines, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK
Ludovic Renault: Macromolecular Machines, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK
Julian Gannon: Macromolecular Machines, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK
Hailey L. Gahlon: Section of Virology and Single Molecule Imaging Group, MRC Clinical Centre, Imperial College London
Abhay Kotecha: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Jin Chuan Zhou: Macromolecular Machines, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK
David Rueda: Section of Virology and Single Molecule Imaging Group, MRC Clinical Centre, Imperial College London
Alessandro Costa: Macromolecular Machines, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract The Cdc45-MCM-GINS (CMG) helicase unwinds DNA during the elongation step of eukaryotic genome duplication and this process depends on the MCM ATPase function. Whether CMG translocation occurs on single- or double-stranded DNA and how ATP hydrolysis drives DNA unwinding remain open questions. Here we use cryo-electron microscopy to describe two subnanometre resolution structures of the CMG helicase trapped on a DNA fork. In the predominant state, the ring-shaped C-terminal ATPase of MCM is compact and contacts single-stranded DNA, via a set of pre-sensor 1 hairpins that spiral around the translocation substrate. In the second state, the ATPase module is relaxed and apparently substrate free, while DNA intimately contacts the downstream amino-terminal tier of the MCM motor ring. These results, supported by single-molecule FRET measurements, lead us to suggest a replication fork unwinding mechanism whereby the N-terminal and AAA+ tiers of the MCM work in concert to translocate on single-stranded DNA.

Date: 2016
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DOI: 10.1038/ncomms10708

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