Balanced proliferation-quiescence decisions are vital during normal development and in tissue homeostasis, and their dysregulation underlies tumorigenesis. Entry into proliferative cycles is driven by Cyclin/Cyclin-dependent kinases (Cdks). Conserved Cdk inhibitors (CKIs) p21^Cip1/Waf1, p27^Kip1, and p57^Kip2 bind to Cyclin/Cdks and inhibit Cdk activity. p27 tyrosine phosphorylation, in response to mitogenic signaling, promotes activation of CyclinD/Cdk4 and CyclinA/Cdk2. Tyrosine phosphorylation is conserved in p21 and p57, although the number of sites differs. We use molecular-dynamics simulations to compare the structural changes in Cyclin/Cdk/CKI trimers induced by single and multiple tyrosine phosphorylation in CKIs and their impact on CyclinD/Cdk4 and CyclinA/Cdk2 activity. Despite shared structural features, CKI binding induces distinct structural responses in Cyclin/Cdks and the predicted effects of CKI tyrosine phosphorylation on Cdk activity are not conserved across CKIs. Our analyses suggest how CKIs may have evolved to be sensitive to different inputs to give context-dependent control of Cdk activity.

平衡的增殖-静止决定在正常发育和组织稳态过程中至关重要，它们的失调是肿瘤发生的基础。进入增殖周期是由细胞周期蛋白/细胞周期蛋白依赖性激酶 (Cdks) 驱动的。保守 Cdk 抑制剂 (CKI) p21 ^Cip1/Waf1、p27 ^Kip1和 p57 ^Kip2与 Cyclin/Cdks 结合并抑制 Cdk 活性。p27 酪氨酸磷酸化响应有丝分裂信号，促进 CyclinD/Cdk4 和 CyclinA/Cdk2 的激活。尽管位点数量不同，但 p21 和 p57 中的酪氨酸磷酸化是保守的。我们使用分子动力学模拟来比较 CKI 中单个和多个酪氨酸磷酸化诱导的 Cyclin/Cdk/CKI 三聚体的结构变化及其对 CyclinD/Cdk4 和 CyclinA/Cdk2 活性的影响。尽管具有共同的结构特征，但 CKI 结合会在 Cyclin/Cdks 中诱导不同的结构反应，并且 CKI 酪氨酸磷酸化对 Cdk 活性的预测影响在 CKI 中并不保守。我们的分析表明，CKI 可能如何进化为对不同输入敏感，从而对 Cdk 活动进行上下文相关的控制。