RT Journal Article
SR Electronic
T1 Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.04.429742
DO 10.1101/2021.02.04.429742
A1 Swadling, Jacob B.
A1 Warnecke, Tobias
A1 Morris, Kyle L.
A1 Barr, Alexis R.
YR 2021
UL http://biorxiv.org/content/early/2021/02/04/2021.02.04.429742.abstract
AB 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 StatementThe authors have declared no competing interest.