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MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis

Author

Listed:
  • Sarah V. Faull

    (Imperial College London)

  • Marta Barbon

    (Imperial College London
    MRC London Institute of Medical Sciences)

  • Audrey Mossler

    (Imperial College London)

  • Zuanning Yuan

    (Van Andel Research Institute)

  • Lin Bai

    (Van Andel Research Institute
    Peking University)

  • L. Maximilian Reuter

    (Imperial College London
    Institute of Molecular Biology (IMB) gGmbH)

  • Alberto Riera

    (Imperial College London)

  • Christian Winkler

    (Imperial College London)

  • Indiana Magdalou

    (Imperial College London)

  • Matthew Peach

    (Imperial College London)

  • Huilin Li

    (Van Andel Research Institute)

  • Christian Speck

    (Imperial College London
    MRC London Institute of Medical Sciences)

Abstract

The eukaryotic helicase MCM2-7, is loaded by ORC, Cdc6 and Cdt1 as a double-hexamer onto replication origins. The insertion of DNA into the helicase leads to partial MCM2-7 ring closure, while ATP hydrolysis is essential for consecutive steps in pre-replicative complex (pre-RC) assembly. Currently it is unknown how MCM2-7 ring closure and ATP-hydrolysis are controlled. A cryo-EM structure of an ORC-Cdc6-Cdt1-MCM2-7 intermediate shows a remodelled, fully-closed Mcm2/Mcm5 interface. The Mcm5 C-terminus (C5) contacts Orc3 and specifically recognises this closed ring. Interestingly, we found that normal helicase loading triggers Mcm4 ATP-hydrolysis, which in turn leads to reorganisation of the MCM2-7 complex and Cdt1 release. However, defective MCM2-7 ring closure, due to mutations at the Mcm2/Mcm5 interface, leads to MCM2-7 ring splitting and complex disassembly. As such we identify Mcm4 as the key ATPase in regulating pre-RC formation. Crucially, a stable Mcm2/Mcm5 interface is essential for productive ATP-hydrolysis-dependent remodelling of the helicase.

Suggested Citation

  • Sarah V. Faull & Marta Barbon & Audrey Mossler & Zuanning Yuan & Lin Bai & L. Maximilian Reuter & Alberto Riera & Christian Winkler & Indiana Magdalou & Matthew Peach & Huilin Li & Christian Speck, 2025. "MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55479-1
    DOI: 10.1038/s41467-024-55479-1
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