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

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, Stephen W. White, Peter Tompa (), Claus A. M. Seidel () and Richard Kriwacki ()
Additional contact information
Maksym Tsytlonok: Vrije Universiteit Brussel
Hugo Sanabria: Clemson University
Yuefeng Wang: St. Jude Children’s Research Hospital
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
Cheon-Gil Park: St. Jude Children’s Research Hospital
Sivaraja Vaithiyalingam: 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
Claus A. M. Seidel: Heinrich-Heine-Universität
Richard Kriwacki: St. Jude Children’s Research Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09446-w

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