Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation.
| Autor: | Swadling JB; Institute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United Kingdom. Electronic address: jacob.swadling@lms.mrc.ac.uk., Warnecke T; Institute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United Kingdom., Morris KL; MRC London Institute of Medical Sciences, London, United Kingdom., Barr AR; Institute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United Kingdom. Electronic address: a.barr@lms.mrc.ac.uk. |
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| Jazyk: | angličtina |
| Zdroj: | Biophysical journal [Biophys J] 2022 Jun 21; Vol. 121 (12), pp. 2312-2329. Date of Electronic Publication: 2022 May 25. |
| DOI: | 10.1016/j.bpj.2022.05.024 |
| Abstrakt: | 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. Competing Interests: Declaration of interests All authors declare they have no competing interests. (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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