Petri Edward T, Errico Alessia, Escobedo Lourdes, Hunt Tim, Basavappa Ravi
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Cell Cycle. 2007 Jun 1;6(11):1342-9. doi: 10.4161/cc.6.11.4297. Epub 2007 Jun 14.
Cyclin B is the key regulatory protein controlling mitosis in all eukaryotes, where it binds cyclin-dependent kinase, cdk1, forming a complex which initiates the mitotic program through phosphorylation of select proteins. Cyclin B regulates the activation, subcellular localization, and substrate specificity of cdk1, and destruction of cyclin B is necessary for mitotic exit. Overexpression of human cyclin B1 has been found in numerous cancers and has been associated with tumor aggressiveness. Here we report the crystal structure of human cyclin B1 to 2.9 A. Comparison of the structure with cyclin A and cyclin E reveals remarkably similar N-terminal cyclin box motifs but significant differences among the C-terminal cyclin box lobes. Divergence in sequence gives rise to unique interaction surfaces at the proposed cyclin B/cdk1 interface as well as the 'RxL' motif substrate binding site on cyclin B. Examination of the structure provides insight into the molecular basis for differential affinities of protein based cyclin/cdk inhibitors such as p27, substrate recognition, and cdk interaction.
细胞周期蛋白B是所有真核生物中控制有丝分裂的关键调节蛋白，它与细胞周期蛋白依赖性激酶cdk1结合，形成一个复合物，通过对特定蛋白质的磷酸化启动有丝分裂程序。细胞周期蛋白B调节cdk1的激活、亚细胞定位和底物特异性，细胞周期蛋白B的降解是有丝分裂退出所必需的。在许多癌症中都发现了人类细胞周期蛋白B1的过表达，并且它与肿瘤侵袭性有关。在此我们报道了人类细胞周期蛋白B1的晶体结构，分辨率达到2.9埃。将该结构与细胞周期蛋白A和细胞周期蛋白E进行比较，发现N端细胞周期蛋白框基序非常相似，但C端细胞周期蛋白框叶之间存在显著差异。序列差异在所提出的细胞周期蛋白B/cdk1界面以及细胞周期蛋白B上的“RxL”基序底物结合位点产生了独特的相互作用表面。对该结构的研究为基于蛋白质的细胞周期蛋白/cdk抑制剂（如p27）的不同亲和力、底物识别和cdk相互作用的分子基础提供了深入了解。
