Abstract
p27Kip1 (p27), which controls eukaryotic cell division through interactions with cyclin-dependent kinases (Cdks), integrates and transduces promitogenic signals from various nonreceptor tyrosine kinases by orchestrating its own phosphorylation, ubiquitination and degradation. Intrinsic flexibility allows p27 to act as a "conduit" for sequential signaling mediated by tyrosine and threonine phosphorylation and ubiquitination. While the structural features of the Cdk/cyclin-binding domain of p27 are understood, how the C-terminal regulatory domain coordinates multistep signaling leading to p27 degradation is poorly understood. We show that the 100-residue p27 C-terminal domain is extended and flexible when p27 is bound to Cdk2/cyclin A. We propose that the intrinsic flexibility of p27 provides a molecular basis for the sequential signal transduction conduit that regulates p27 degradation and cell division. Other intrinsically unstructured proteins possessing multiple sites of posttranslational modification may participate in similar signaling conduits.
Original language | English |
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Pages (from-to) | 827-838 |
Number of pages | 12 |
Journal | Journal of Molecular Biology |
Volume | 376 |
Issue number | 3 |
DOIs | |
State | Published - Feb 22 2008 |
Funding
The authors acknowledge Dr. Peter Schuck (National Institutes of Health, Bethesda, MD) for helpful discussion on the analysis of analytical centrifugation data and Yiming Mo (Oak Ridge National Laboratory, Oak Ridge, TN) for assistance in collecting SAXS data. This work was supported by the American Lebanese Syrian Associated Charities (ALSAC), National Cancer Institute (2R01CA082491 to R.W.K.), and a Cancer Center (CORE) Support grant (5P30CA021765, St. Jude Children's Research Hospital). SAXS studies were supported by the Oak Ridge Center for Structural Molecular Biology (KP1102010) of the Office of Biological and Environmental Research of the U.S. Department of Energy, under contract DE-AC05-00OR22725 with Oak Ridge National Laboratory, managed and operated by UT-Batelle, LLC. The submitted manuscript has been authored by a contractor of the U.S. Government under contract DE-AC05-00OR22725. Accordingly, the U.S. government retains a nonexclusive royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. government purposes.
Keywords
- cell cycle
- cyclin-dependent kinase inhibitor
- disordered protein
- intrinsically unstructured protein
- p27