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

## TL;DR

This study reveals how the intrinsically disordered protein p27 dynamically anticipates and integrates multiple phosphorylation signals when bound to Cdk2/cyclin A, regulating cell cycle progression through allosteric mechanisms.

## Contribution

It uncovers the role of intrinsic flexibility and dynamic anticipation in p27 for signal integration and regulation of Cdk2 activity within cell cycle control.

## Key findings

- p27 samples lowly-populated conformations that anticipate phosphorylation events.
- Phosphorylation of p27 relieves inhibition and promotes cell cycle progression.
- Intrinsic dynamics enable p27 to process multiple signaling inputs even when bound.

## Abstract

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.

---
Source: https://tomesphere.com/paper/1812.07009