Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation
| Autor: | Tsytlonok, Maksym, Sanabria, Hugo, Wang, Yuefeng, Felekyan, Suren, Hemmen, Katherina, Phillips, Aaron, Yun, Mi-Kyung, Waddell, Brett, Park, Cheon-Gil, Vaithiyalingam, Sivaraja, Iconaru, Luigi, White, Stephen W., Tompa, Peter, Seidel, Claus A. M., Kriwacki, Richard |
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| Rok vydání: | 2018 |
| Předmět: | |
| Druh dokumentu: | Working Paper |
| DOI: | 10.1038/s41467-019-09446-w |
| Popis: | p27$^{Kip1}$ (p27) is an intrinsically disordered protein (IDP) that folds upon binding to cyclin-dependent kinase (Cdk)$/$cyclin complexes (e.g., Cdk2$/$cyclin A), inhibiting their catalytic activity and causing cell cycle arrest. However, cell division progresses when stably Cdk2$/$cyclin A-bound p27 is phosphorylated on one or two structurally occluded tyrosine residues $[$tyrosines 88 (Y88) and 74 (Y74)$]$ and a distal threonine residue $[$threonine 187 (T187)$]$. These events trigger ubiquitination and degradation of p27, fully activating Cdk2$/$cyclin A to drive cell division. Using an integrated approach comprising structural, biochemical, biophysical and single-molecule fluorescence methods, we show that Cdk2$/$cyclin A-bound p27 samples lowly-populated conformations that dynamically anticipate the sequential steps of this signaling cascade. "Dynamic anticipation" provides access to the non-receptor tyrosine kinases, BCR-ABL and Src, which sequentially phosphorylate Y88 and Y74 and promote intra-assembly phosphorylation (of p27) on distal T187. Tyrosine phosphorylation also allosterically relieves p27-dependent inhibition of substrate binding to Cdk2$/$cyclin A, a phenomenon we term "cross-complex allostery". 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, as exemplified by hyper-active BCR-ABL and Src in certain cancers. Comment: 35 pages, 5 figures, supporting information 37 pages |
| Databáze: | arXiv |
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