Kurniawan Fredy, Shi Ke, Kurahashi Kayo, Bielinsky Anja-Katrin, Aihara Hideki
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
iScience. 2018 May 25;3:102-109. doi: 10.1016/j.isci.2018.04.011.
Cdc45 plays a critical role at the core of the eukaryotic DNA replisome, serving as an essential scaffolding component of the replicative helicase holoenzyme Cdc45-MCM-GINS (CMG) complex. A 1.66-Å-resolution crystal structure of the full-length Cdc45 protein from shows a protein fold similar to that observed previously for human Cdc45 in its active conformation, featuring the overall disk-like monomer shape and intimate contacts between the N- and C-terminal DHH domains. However, the Cdc45 structure shows several unique features, including a distinct orientation of the C-terminal DHHA1 domain, concomitant disordering of the adjacent protruding α-helical segment implicated in DNA polymerase ε interactions, and a unique conformation of the GINS/Mcm5-binding loop. These structural observations collectively suggest the possibility that Cdc45 can sample multiple conformations corresponding to different functional states. We propose that such conformational switch of Cdc45 may allow regulation of protein-protein interactions important in DNA replication.
Cdc45在真核生物DNA复制体的核心发挥着关键作用，作为复制解旋酶全酶Cdc45-MCM-GINS（CMG）复合物的重要支架成分。来自[具体来源未给出]的全长Cdc45蛋白的1.66埃分辨率晶体结构显示出一种与之前观察到的处于活性构象的人类Cdc45相似的蛋白折叠，其特征为整体呈盘状的单体形状以及N端和C端DHH结构域之间的紧密接触。然而，[具体物种未给出]的Cdc45结构显示出几个独特特征，包括C端DHHA1结构域的独特取向、与DNA聚合酶ε相互作用相关的相邻突出α螺旋片段的伴随无序，以及GINS/Mcm5结合环的独特构象。这些结构观察结果共同表明Cdc45可能具有对应不同功能状态的多种构象的可能性。我们提出Cdc45的这种构象转换可能允许对DNA复制中重要的蛋白质-蛋白质相互作用进行调控。
