ArticleScientific reports2016
Mechanism of p27 Unfolding for CDK2 Reactivation.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 18 citations in OpenAlex.
- CIP/KIP and INK4 families as hostages of oncogenic signaling.Cell division · 2024Review
- Article
- An inventory of crosstalk between ubiquitination and other post-translational modifications in orchestrating cellular processes.iScience · 2023Review
- Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation.Biophysical journal · 2022Article
- p27Cells · 2021Review
- Protein Dynamics Enables Phosphorylation of Buried Residues in Cdk2/Cyclin-A-Bound p27.Biophysical journal · 2020Article
- ZNF703 is Overexpressed in Papillary Thyroid Carcinoma Tissues and Mediates K1 Cell Proliferation.Pathology oncology research : POR · 2020Article
- CPT1 regulates the proliferation of pulmonary artery smooth muscle cells through the AMPK-p53-p21 pathway in pulmonary arterial hypertension.Molecular and cellular biochemistry · 2019Article
- The relationship between cervical precancerous lesion galectin-3 and p27 protein expression and clinical prognosis.Oncology letters · 2018Article
- Structural prediction of the interaction of the tumor suppressor p27BMC bioinformatics · 2017Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cell-cycle regulatory protein, CDK2 is active when bound to its complementary partner protein, CyclinA or E. Recent discovery of the Kip/Cip family of proteins has indicated that the activity of CDK2 is also regulated by a member protein, p27. Although, the mechanism of CDK2 inhibition by p27 binding is known from crystal structure, little is known about the mechanism of CDK2 reactivation. Here, we execute classical and accelerated molecular dynamics simulations of unphosphorylated- and phosphorylated-p27 bound CDK2/CyclinA to unravel the CDK2 reactivation mechanism at molecular-to-atomic detail. Results suggest that the phosphorylation of p27 Y88 residue (pY88-p27) first disrupts the p27/CDK2 hybrid β-sheet and subsequently ejects the p27 310 helix from CDK2 catalytic cleft. The unbinding of p27 from CDK2/CyclinA complex, thus, follows a two-step unfolding mechanism, where the 310 helix ejection constitutes the rate-limiting step. Interestingly, the unfolding of p27 leaves CDK2/CyclinA in an active state, where the prerequisite CDK2-CyclinA interfacial contacts were regained and ATP achieved its native position for smooth transfer of phosphate. Our findings match very well with NMR chemical shift data that indicated the flip-out of p27 310 helix from CDK2 pocket and kinetic experiments that exhibited significant kinase activity of CDK2 when saturated with pY88-p27.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.