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

Jiaxuan Cheng, Ningning Li, Yunjing Huo, Shangyu Dang, Bik-Kwoon Tye (), Ning Gao () and Yuanliang Zhai ()
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Jiaxuan Cheng: Peking University
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
Ning Gao: Peking University
Yuanliang Zhai: The University of Hong Kong

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29070-5

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