Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation.

TitleDynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation.
Publication TypeJournal Article
Year of Publication2019
AuthorsTsytlonok, M., H. Sanabria, Y. Wang, S. Felekyan, K. Hemmen, A. H. Phillips, M-K. Yun, B. M Waddell, C-G. Park, S. Vaithiyalingam, L. Iconaru, S. W. White, P. Tompa, C. A. M. Seidel, and R. Kriwacki
JournalNat Commun
Volume10
Issue1
Pagination1676
Date Published2019 04 11
ISSN2041-1723
KeywordsCell Division, Crystallography, X-Ray, Cyclin A, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p27, Fusion Proteins, bcr-abl, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Proteolysis, Recombinant Proteins, Signal Transduction, src-Family Kinases, Threonine, Tyrosine
Abstract

p27 is an intrinsically disordered protein (IDP) that inhibits cyclin-dependent kinase (Cdk)/cyclin complexes (e.g., Cdk2/cyclin A), causing cell cycle arrest. Cell division progresses when stably Cdk2/cyclin A-bound p27 is phosphorylated on one or two structurally occluded tyrosine residues and a distal threonine residue (T187), triggering degradation of p27. Here, using an integrated biophysical approach, we show that Cdk2/cyclin A-bound p27 samples lowly-populated conformations that provide access to the non-receptor tyrosine kinases, BCR-ABL and Src, which phosphorylate Y88 or Y88 and Y74, respectively, thereby promoting intra-assembly phosphorylation (of p27) on distal T187. Even when tightly bound to Cdk2/cyclin A, intrinsic flexibility enables p27 to integrate and process signaling inputs, and generate outputs including altered Cdk2 activity, p27 stability, and, ultimately, cell cycle progression. Intrinsic dynamics within multi-component assemblies may be a general mechanism of signaling by regulatory IDPs, which can be subverted in human disease.

DOI10.1038/s41467-019-09446-w
Alternate JournalNat Commun
PubMed ID30976006
PubMed Central IDPMC6459857
Grant ListP20 GM121342 / GM / NIGMS NIH HHS / United States
R01 GM083159 / GM / NIGMS NIH HHS / United States
P20GM121342 / NH / NIH HHS / United States
R01MH08192311 / NH / NIH HHS / United States
P30 CA021765 / CA / NCI NIH HHS / United States
R01 CA082491 / CA / NCI NIH HHS / United States
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