Interaction of Circadian Clock Proteins CRY1 and PER2 Is Modulated by Zinc Binding and Disulfide Bond Formation
Interaction of Circadian Clock Proteins CRY1 and PER2 Is Modulated by Zinc Binding and Disulfide Bond Formation
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DOI：
10.1016/j.cell.2014.03.057
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发表时间：
2014-05-22
期刊：
影响因子：
64.5
通讯作者：
Wolf, Eva
中科院分区：
文献类型：
--
作者：
Schmalen, Ira;Reischl, Silke;Wolf, Eva
周期蛋白（PER）是哺乳动物生物钟的重要组成部分。它们与隐色素（CRY）形成复合物，隐色素负向调节时钟/ bmal1依赖的时钟和时钟控制基因的转激活。为了确定哺乳动物CRY/PER复合物在生物钟中的作用，我们确定了一个复合物的晶体结构，该复合物包括小鼠CRY1 （mCRY1）的光解酶同源区和小鼠c端PER2 （mPER2）片段。mPER2缠绕在螺旋状mCRY1结构域周围，覆盖FBXL3和CLOCK/BMAL1的结合位点，但不覆盖FAD结合袋。我们的结构在一个界面上发现了一个意想不到的锌离子，这稳定了mCRY1-mPER2在体内的相互作用。我们提供的证据表明，mCRY1/mPER2复合物的形成是由锌结合和mCRY1二硫键形成的相互作用调节的，这可能受到细胞氧化还原状态的影响。我们的研究可能允许昼夜节律和代谢调节剂的发展。
Period (PER) proteins are essential components of the mammalian circadian clock. They form complexes with cryptochromes (CRY), which negatively regulate CLOCK/BMAL1-dependent transactivation of clock and clock-controlled genes. To define the roles of mammalian CRY/PER complexes in the circadian clock, we have determined the crystal structure of a complex comprising the photolyase homology region of mouse CRY1 (mCRY1) and a C-terminal mouse PER2 (mPER2) fragment. mPER2 winds around the helical mCRY1 domain covering the binding sites of FBXL3 and CLOCK/BMAL1, but not the FAD binding pocket. Our structure revealed an unexpected zinc ion in one interface, which stabilizes mCRY1-mPER2 interactions in vivo. We provide evidence that mCRY1/mPER2 complex formation is modulated by an interplay of zinc binding and mCRY1 disulfide bond formation, which may be influenced by the redox state of the cell. Our studies may allow for the development of circadian and metabolic modulators.