Pin1 catalyzes conformational changes of Thr-187 in p27Kip1 and mediates its stability through a polyubiquitination process.

The cis-trans peptidylprolyl isomerase Pin1 plays a critical role in regulating a subset of phosphoproteins by catalyzing conformational changes on the phosphorylated Ser/Thr-Pro motifs. The phosphorylation-directed ubiquitination is one of the major mechanisms to regulate the abundance of p27(Kip1). In this study, we demonstrate that Pin1 catalyzes the cis-trans conformational ...
changes of p27(Kip1) and further mediates its stability through the polyubiquitination mechanism. Our results show that the phosphorylated Thr-187-Pro motif in p27(Kip1) is a key Pin1-binding site. In addition, NMR analyses show that this phosphorylated Thr-187-Pro site undergoes conformational change catalyzed by Pin1. Moreover, in Pin1 knock-out mouse embryonic fibroblasts, p27(Kip1) has a shorter lifetime and displays a higher degree of polyubiquitination than in Pin1 wild-type mouse embryonic fibroblasts, suggesting that Pin1 plays a critical role in regulating p27(Kip1) degradation. Additionally, Pin1 dramatically reduces the interaction between p27(Kip1) and Cks1, possibly via isomerizing the cis-trans conformation of p27(Kip1). Our study thus reveals a novel regulatory mechanism for p27(Kip1) stability and sheds new light on the biological function of Pin1 as a general regulator of protein stability.
Mesh Terms:
Amino Acid Motifs, Animals, CDC2-CDC28 Kinases, Carrier Proteins, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Embryo, Mammalian, Fibroblasts, Hela Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Peptidylprolyl Isomerase, Phosphorylation, Protein Stability, Threonine, Ubiquitination
J. Biol. Chem.
Date: Sep. 04, 2009
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