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Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase

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  • Jiaxuan Cheng

    (Peking University
    National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Ningning Li

    (Peking University)

  • Yunjing Huo

    (The University of Hong Kong)

  • Shangyu Dang

    (The Hong Kong University of Science & Technology)

  • Bik-Kwoon Tye

    (Institute for Advanced Study, The Hong Kong University of Science & Technology
    Cornell University)

  • Ning Gao

    (Peking University
    Peking University)

  • Yuanliang Zhai

    (The University of Hong Kong)

Abstract

The Dbf4-dependent kinase Cdc7 (DDK) regulates DNA replication initiation by phosphorylation of the MCM double hexamer (MCM-DH) to promote helicase activation. Here, we determine a series of cryo electron microscopy (cryo-EM) structures of yeast DDK bound to the MCM-DH. These structures, occupied by one or two DDKs, differ primarily in the conformations of the kinase core. The interactions of DDK with the MCM-DH are mediated exclusively by subunit Dbf4 straddling across the hexamer interface on the three N-terminal domains (NTDs) of subunits Mcm2, Mcm6, and Mcm4. This arrangement brings Cdc7 close to its only essential substrate, the N-terminal serine/threonine-rich domain (NSD) of Mcm4. Dbf4 further displaces the NSD from its binding site on Mcm4-NTD, facilitating an immediate targeting of this motif by Cdc7. Moreover, the active center of Cdc7 is occupied by a unique Dbf4 inhibitory loop, which is disengaged when the kinase core assumes wobbling conformations. This study elucidates the versatility of Dbf4 in regulating the ordered multisite phosphorylation of the MCM-DH by Cdc7 kinase during helicase activation.

Suggested Citation

  • Jiaxuan Cheng & Ningning Li & Yunjing Huo & Shangyu Dang & Bik-Kwoon Tye & Ning Gao & Yuanliang Zhai, 2022. "Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29070-5
    DOI: 10.1038/s41467-022-29070-5
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    References listed on IDEAS

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    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.

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