Harbour J W, Luo R X, Dei Santi A, Postigo A A, Dean D C
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cell. 1999 Sep 17;98(6):859-69. doi: 10.1016/s0092-8674(00)81519-6.
We present evidence that phosphorylation of the C-terminal region of Rb by Cdk4/6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by Rb. This facilitates a second interaction that leads to phosphorylation of the pocket by Cdk2 and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of Rb by Cdk4/6 and Cdk2. Cdk4/6 is activated early in G1, blocking active repression by Rb. However, it is not until near the end of G1, when cyclin E is expressed and Cdk2 is activated, that Rb is prevented from binding and inactivating E2F.
我们提供的证据表明，细胞周期蛋白依赖性激酶4/6（Cdk4/6）介导的视网膜母细胞瘤蛋白（Rb）C末端区域的磷酸化引发了C末端区域与中央口袋之间连续的分子内相互作用。最初的相互作用将组蛋白去乙酰化酶从口袋中置换出来，阻断了Rb的活性转录抑制作用。这促进了第二种相互作用，导致Cdk2对口袋进行磷酸化并破坏口袋结构。这些分子内相互作用为Cdk4/6和Cdk2对Rb的顺序磷酸化提供了分子基础。Cdk4/6在G1期早期被激活，阻断Rb的活性抑制作用。然而，直到G1期末期，当细胞周期蛋白E表达且Cdk2被激活时，Rb才被阻止结合并使E2F失活。
