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保守的 Cdk 抑制剂对酪氨酸磷酸化表现出独特的结构响应。

Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation.

机构信息

Institute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United Kingdom.

Institute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United Kingdom.

出版信息

Biophys J. 2022 Jun 21;121(12):2312-2329. doi: 10.1016/j.bpj.2022.05.024. Epub 2022 May 25.

DOI:10.1016/j.bpj.2022.05.024
PMID:35614852
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9279356/
Abstract

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, p27, and p57 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.

摘要

平衡的增殖-静止决策在正常发育和组织稳态中至关重要，其失调是肿瘤发生的基础。进入增殖周期是由细胞周期蛋白/细胞周期依赖性激酶（Cdks）驱动的。保守的细胞周期蛋白依赖性激酶抑制剂（CKIs）p21、p27 和 p57 与细胞周期蛋白/Cdks 结合并抑制 Cdk 活性。p27 酪氨酸磷酸化响应有丝分裂信号，促进细胞周期蛋白 D/Cdk4 和细胞周期蛋白 A/Cdk2 的激活。p21 和 p57 中都存在酪氨酸磷酸化，尽管磷酸化位点的数量不同。我们使用分子动力学模拟来比较 CKIs 中单和多个酪氨酸磷酸化诱导的细胞周期蛋白/Cdk/CKI 三聚体的结构变化及其对细胞周期蛋白 D/Cdk4 和细胞周期蛋白 A/Cdk2 活性的影响。尽管具有共享的结构特征，但 CKI 结合在细胞周期蛋白/Cdks 中诱导不同的结构响应，并且 CKI 酪氨酸磷酸化对 Cdk 活性的预测影响在 CKIs 之间并不保守。我们的分析表明 CKIs 如何进化以对不同的输入敏感，从而对 Cdk 活性进行上下文相关的控制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/f6ec9cfcf0d7/gr11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/d5dbe435c291/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/0a6bf053d556/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/78bf7f7290e2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/f930876608e2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/f5498e29d0cc/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/d38392301689/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/ef853a681c8c/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/d072cb3b2ebe/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/cd0248af5c78/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/7d7f69016be6/gr10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/f6ec9cfcf0d7/gr11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/d5dbe435c291/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/0a6bf053d556/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/78bf7f7290e2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/f930876608e2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/f5498e29d0cc/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/d38392301689/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/ef853a681c8c/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/d072cb3b2ebe/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/cd0248af5c78/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/7d7f69016be6/gr10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e049/9279356/f6ec9cfcf0d7/gr11.jpg

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Functional Versatility of the CDK Inhibitor p57.细胞周期蛋白依赖性激酶抑制剂p57的功能多样性
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