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

Author

Listed:
  • Maksym Tsytlonok

    (Vrije Universiteit Brussel)

  • Hugo Sanabria

    (Clemson University
    Heinrich-Heine-Universität)

  • Yuefeng Wang

    (St. Jude Children’s Research Hospital
    West Cancer Center and Research Institute)

  • Suren Felekyan

    (Heinrich-Heine-Universität)

  • Katherina Hemmen

    (Heinrich-Heine-Universität)

  • Aaron H. Phillips

    (St. Jude Children’s Research Hospital)

  • Mi-Kyung Yun

    (St. Jude Children’s Research Hospital)

  • M. Brett Waddell

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Cheon-Gil Park

    (St. Jude Children’s Research Hospital)

  • Sivaraja Vaithiyalingam

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Luigi Iconaru

    (St. Jude Children’s Research Hospital)

  • Stephen W. White

    (St. Jude Children’s Research Hospital)

  • Peter Tompa

    (Vrije Universiteit Brussel
    Research Centre for Natural Sciences of the Hungarian Academy of Sciences)

  • Claus A. M. Seidel

    (Heinrich-Heine-Universität)

  • Richard Kriwacki

    (St. Jude Children’s Research Hospital
    University of Tennessee Health Sciences Center)

Abstract

p27Kip1 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.

Suggested Citation

  • Maksym Tsytlonok & Hugo Sanabria & Yuefeng Wang & Suren Felekyan & Katherina Hemmen & Aaron H. Phillips & Mi-Kyung Yun & M. Brett Waddell & Cheon-Gil Park & Sivaraja Vaithiyalingam & Luigi Iconaru & S, 2019. "Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09446-w
    DOI: 10.1038/s41467-019-09446-w
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    Cited by:

    1. Victoria I. Cushing & Adrian F. Koh & Junjie Feng & Kaste Jurgaityte & Alexander Bondke & Sebastian H. B. Kroll & Marion Barbazanges & Bodo Scheiper & Ash K. Bahl & Anthony G. M. Barrett & Simak Ali &, 2024. "High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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