FC0036
p27^Kip1  -  Cdk2/cyclin

Biological function
p27^Kip1 (p27), which controls eukaryotic cell division through interactions with cyclin-dependent kinases (Cdks).

Structural evidence
By NMR and SAXS it is shown that the 100-residue p27 C-terminal domain is extended and disordered when p27 is bound to Cdk2/cyclin A. The extended conformation is partly due to electrostatic repulsion between the globular core and the tail.

Biochemical evidence
The level of p27, which is controlled by translational regulation and ubiquitination-dependent proteolysis, must drop for Cdk2 complexes to be fully activated and for cell division to progress. Ubiquitination of p27 at the G1/S transition is regulated by a two-step mechanism that involves phosphorylation of p27, first on tyrosine 88 (Y88) by one of several nonreceptor tyrosine kinases (NRTKs) and second on threonine 187 (T187) by Cdk2.

Structure/Mechanism
Ubiquitination of p27 by SCF/Skp2 requires phosphorylation at T187. The Cdk2 active site however is blocked by Y88 according to the crystal structure. The fluctuation of Y88 makes the active site of the kinase accessible. The disorder of the C terminal tail enables T187 to interact with the active site and get phosphorylated. The ubiquitination and subsequent degradation of p27 allowing the progression from G1 to S phase.

Mechanism category
competitive binding

Posttranslational modification
Ubiquitination p27 by SCF/Skp2 requires phosphorylation at T187.

Significance
The fuzzy tail is proposed to serve as a sequential signal transduction conduit that regulates p27 degradation and cell division.

Medical relevance
Enhanced ubiquitination-mediated degradation of p27 is common in human tumors.