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Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation

Jacob B. Swadling, Tobias Warnecke, Kyle L. Morris, Alexis R. Barr
doi: https://doi.org/10.1101/2021.02.04.429742
Jacob B. Swadling
†Institute of Clinical Sciences, Imperial College London, UK
‡MRC London Institute of Medical Sciences, UK
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Tobias Warnecke
†Institute of Clinical Sciences, Imperial College London, UK
‡MRC London Institute of Medical Sciences, UK
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Kyle L. Morris
‡MRC London Institute of Medical Sciences, UK
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Alexis R. Barr
†Institute of Clinical Sciences, Imperial College London, UK
‡MRC London Institute of Medical Sciences, UK
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  • For correspondence: a.barr@lms.mrc.ac.uk
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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), p21Cip1/Waf1, p27Kip1 and p57Kip2, bind to Cyclin/Cdks and inhibit Cdk activity. p27 tyrosine phosphorylation, in response to mitogenic signalling, 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 Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* E-mail: jacob.swadling{at}lms.mrc.ac.uk; a.barr{at}lms.mrc.ac.uk

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 04, 2021.
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Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation
Jacob B. Swadling, Tobias Warnecke, Kyle L. Morris, Alexis R. Barr
bioRxiv 2021.02.04.429742; doi: https://doi.org/10.1101/2021.02.04.429742
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Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation
Jacob B. Swadling, Tobias Warnecke, Kyle L. Morris, Alexis R. Barr
bioRxiv 2021.02.04.429742; doi: https://doi.org/10.1101/2021.02.04.429742

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