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

Author

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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
    National Institute for Biological Standards and Control, Microscopy and Imaging, Blanche Lane, South Mimms EN6 3QG, UK)

  • Julian Gannon

    (Macromolecular Machines, Clare Hall Laboratory, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK
    Present address: Synthetic and Systems Biochemistry of the Microtubule Cytoskeleton, Lincoln’s Inn Fields Laboratory, The Francis Crick Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, 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)

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.

Suggested Citation

  • Ferdos Abid Ali & Ludovic Renault & Julian Gannon & Hailey L. Gahlon & Abhay Kotecha & Jin Chuan Zhou & David Rueda & Alessandro Costa, 2016. "Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10708
    DOI: 10.1038/ncomms10708
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    Cited by:

    1. Zhichun Xu & Jianrong Feng & Daqi Yu & Yunjing Huo & Xiaohui Ma & Wai Hei Lam & Zheng Liu & Xiang David Li & Toyotaka Ishibashi & Shangyu Dang & Yuanliang Zhai, 2023. "Synergism between CMG helicase and leading strand DNA polymerase at replication fork," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Daniel Ramírez Montero & Humberto Sánchez & Edo Veen & Theo Laar & Belén Solano & John F. X. Diffley & Nynke H. Dekker, 2023. "Nucleotide binding halts diffusion of the eukaryotic replicative helicase during activation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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