Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase.
Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase.
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DOI：
10.1038/s41467-022-29070-5
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发表时间：
2022-03-16
影响因子：
16.6
通讯作者：
Zhai Y
中科院分区：
文献类型：
--
作者：
Cheng J;Li N;Huo Y;Dang S;Tye BK;Gao N;Zhai Y
Dbf 4依赖性激酶Cdc 7（DDK）通过磷酸化MCM双六聚体（MCM-DH）以促进解旋酶活化来调节DNA复制起始。在这里，我们确定了一系列的冷冻电子显微镜（cryo-EM）结构的酵母DDK结合MCM-DH。这些结构被一个或两个DDK占据，主要区别在于激酶核心的构象。DDK与MCM-DH的相互作用仅由亚基Dbf 4介导，Dbf 4跨越亚基Mcm 2、Mcm 6和Mcm 4的三个N-末端结构域（NTD）上的六聚体界面。这种安排使Cdc 7接近其唯一的基本底物，N-末端丝氨酸/苏氨酸丰富的结构域（NSD）的Mcm 4。Dbf 4进一步从其在Mcm 4-NTD上的结合位点置换NSD，促进Cdc 7立即靶向该基序。此外，Cdc 7的活性中心被一个独特的Dbf 4抑制环占据，当激酶核心呈现摇摆构象时，该抑制环被分离。这项研究阐明了Dbf 4在解旋酶激活过程中通过Cdc 7激酶调节MCM-DH的有序多位点磷酸化的多功能性。Dbf 4依赖性激酶Cdc 7（DDK）对于真核DNA复制至关重要。在这里，作者提出了一系列的cryo-EM结构，阐明了这种激酶的多功能性，发挥其重要目标的有序磷酸化，以促进复制起始。
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. The Dbf4-dependent kinase Cdc7 (DDK) is essential for eukaryotic DNA replication. Here, the authors present a series of cryo-EM structures elucidating the versatility of this kinase in exerting an ordered phosphorylation of its essential target to promote replication initiation.
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影响因子：
3.3
作者：
Bell SP;Labib K
通讯作者：
Labib K
影响因子：
16
作者：
Baretic, Domagoj;Jenkyn-Bedford, Michael;Yeeles, Joseph T. P.
通讯作者：
Yeeles, Joseph T. P.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
16.6
作者：
Abid Ali F;Douglas ME;Locke J;Pye VE;Nans A;Diffley JFX;Costa A
通讯作者：
Costa A
影响因子：
7.7
作者：
Abd Wahab, Syafiq;Remus, Dirk
通讯作者：
Remus, Dirk