Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation
| العنوان: | Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation |
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| المؤلفون: | Mi-Kyung Yun, Maksym Tsytlonok, Peter Tompa, Sivaraja Vaithiyalingam, Suren Felekyan, Claus A. M. Seidel, Aaron H. Phillips, Luigi I. Iconaru, Yuefeng Wang, Hugo Sanabria, Stephen W. White, M. Brett Waddell, Richard W. Kriwacki, Katherina Hemmen, Cheon-Gil Park |
| المصدر: | Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) Nature Communications |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Threonine, 0301 basic medicine, Quantitative Biology - Subcellular Processes, Cell division, Cyclin A, Fusion Proteins, bcr-abl, General Physics and Astronomy, 02 engineering and technology, Crystallography, X-Ray, Quantitative Biology - Quantitative Methods, chemistry.chemical_compound, Phosphorylation, lcsh:Science, Quantitative Methods (q-bio.QM), Multidisciplinary, biology, Chemistry, 021001 nanoscience & nanotechnology, Recombinant Proteins, Cell biology, src-Family Kinases, 0210 nano-technology, Tyrosine kinase, Cell Division, Cyclin-Dependent Kinase Inhibitor p27, Protein Binding, Signal Transduction, Proto-oncogene tyrosine-protein kinase Src, Science, Molecular Dynamics Simulation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cyclin-dependent kinase, Subcellular Processes (q-bio.SC), Cyclin-Dependent Kinase 2, Cyclin-dependent kinase 2, Tyrosine phosphorylation, Biomolecules (q-bio.BM), General Chemistry, Protein Structure, Tertiary, 030104 developmental biology, Quantitative Biology - Biomolecules, FOS: Biological sciences, Proteolysis, Mutagenesis, Site-Directed, biology.protein, Tyrosine, lcsh:Q, Protein Processing, Post-Translational |
| الوصف: | 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. 35 pages, 5 figures, supporting information 37 pages |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aebf5b582a25ff50bd576925e3ed1b6aTest http://arxiv.org/abs/1812.07009Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....aebf5b582a25ff50bd576925e3ed1b6a |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |