p27 binds cyclin–CDK complexes through a sequential mechanism involving binding-induced protein folding

Lacy, Eilyn R.; Filippov, Igor V.; Lewis, William; Otieno, Steve; Xiao, Limin; Weiss, Sonja; Hengst, Ludger; Kriwacki, Richard W.

doi:10.1038/nsmb746

Cited by 282 publications

(428 citation statements)

References 52 publications

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“…Hydrodynamic and spectroscopic analyses indicate that human p57 Kip2 lacks a stable helical and b-sheet structure, although the formation of a secondary structure cannot be precluded (50). On the basis of these findings, p57 Kip2 joins the most-investigated p27 Kip1 and its sibling p21 Cip1 in being considered highly unfolded molecules (51)(52)(53)(54).…”

Section: P57 Kip2 Proteinmentioning

confidence: 99%

p57Kip2 and Cancer: Time for a Critical Appraisal

Borriello

Caldarelli

Bencivenga

et al. 2011

Molecular Cancer Research

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p57Kip2 is a cyclin-dependent kinase inhibitor belonging to the Cip/Kip family, which also includes p21Cip1 and p27Kip1. So far, p57Kip2 is the least-studied Cip/Kip protein, and for a long time its relevance has been related mainly to its unique role in embryogenesis. Moreover, genetic and molecular studies on animal models and patients with Beckwith-Wiedemann syndrome have shown that alterations in CDKN1C (the p57Kip2 encoding gene) have functional relevance in the pathogenesis of this disease. Recently, a number of investigations have identified and characterized heretofore unexpected roles for p57Kip2. The protein appears to be critically involved in initial steps of cell and tissue differentiation, and particularly in neuronal development and erythropoiesis. Intriguingly, p27Kip1, the Cip/Kip member that is most homologous to p57Kip2, is primarily involved in the process of cell cycle exit. p57Kip2 also plays a critical role in controlling cytoskeletal organization and cell migration through its interaction with LIMK-1. Furthermore, p57Kip2 appears to modulate genome expression. Finally, accumulating evidence indicates that p57Kip2 protein is frequently downregulated in different types of human epithelial and nonepithelial cancers as a consequence of genetic and epigenetic events. In summary, the emerging picture is that several aspects of p57Kip2's functions are only poorly clarified. This review represents an appraisal of the data available on the p57Kip2 gene and protein structure, and its role in human physiology and pathology. We particularly focus our attention on p57Kip2 changes in cancers and pharmacological approaches for modulating p57Kip2 levels. Mol Cancer Res; 9(10); 1269–84. ©2011 AACR.

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Section: P57 Kip2 Proteinmentioning

confidence: 99%

p57Kip2 and Cancer: Time for a Critical Appraisal

Borriello

Caldarelli

Bencivenga

et al. 2011

Molecular Cancer Research

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“…Some well-known examples include the phosphorylated kinase-inducible domain (pKID) of the cAMP responsive element binding protein (CREB), 1 the transcriptional activation domain structural preferences. For example, NMR studies demonstrated that the linker helix of p27 Kip1 has a nascent secondary structure in its free state 4 although it is largely unstructured in solution. 5 It is increasingly apparent that residual structure of IUPs plays crucial roles in molecular recognition.…”

Section: Introductionmentioning

confidence: 99%

Residual structure within the disordered C‐terminal segment of p21^{Waf1/Cip1/Sdi1} and its implications for molecular recognition

et al. 2009

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Probably the most unusual class of proteins in nature is the intrinsically unstructured proteins (IUPs), because they are not structured yet play essential roles in protein-protein signaling. Many IUPs can bind different proteins, and in many cases, adopt different bound conformations. The p21 protein is a small IUP (164 residues) that is ubiquitous in cellular signaling, for example, cell cycle control, apoptosis, transcription, differentiation, and so forth; it binds to approximately 25 targets. How does this small, unstructured protein recognize each of these targets with high affinity? Here, we characterize residual structural elements of the C-terminal segment of p21 encompassing residues 145-164 using a combination of NMR measurements and molecular dynamics simulations. The N-terminal half of the peptide has a significant helical propensity which is recognized by calmodulin while the C-terminal half of the peptide prefers extended conformations that facilitate binding to the proliferating cell nuclear antigen (PCNA). Our results suggest that the final bound conformations of p21 (145-164) pre-exist in the free peptide even without its binding partners. While the conformational flexibility of the p21 peptide is essential for adapting to diverse binding environments, the intrinsic structural preferences of the free peptide enable promiscuous yet high affinity binding to a diverse array of molecular targets.

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“…At high concentration of competing ligand, k obs will approach k off . There are several methods available to measure rate constants of which the currently most common for IDPs (and folded proteins) are stopped-flow spectroscopy 6 and surface plasmon resonance, 7 but temperature jump, 8 and fluorescence correlation spectroscopy 9 have also been used. NMR transverse relaxation dispersion 10,11 has also emerged as a powerful method to obtain site resolved information about the thermodynamics, kinetics, and chemical shift differences for proteins undergoing conformational exchange on the µs-ms timescale.…”

Section: Introductionmentioning

confidence: 99%

The binding mechanisms of intrinsically disordered proteins

Dogan

Gianni

Jemth

2014

Phys. Chem. Chem. Phys.

131

134

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Likewise, affinities span from pM to µM suggesting that the low-affinity highspecificity concept for IDPs is not straightforward.Overall, it appears as binding precedes global folding although secondary structure elements such as helices may form before the protein-protein interaction. Short IDPs bind in apparent two-state reactions whereas larger IDPs often display complex multistep binding reactions. While the two extreme cases of two-step binding (conformational selection and induced fit) or their combination into a square mechanism is an attractive model in theory, it is too simplistic in practice. Experiment and simulation suggest a more complex energy landscape in which IDPs bind targets through a combination of conformational selection before binding (e.g., secondary structure formation) and induced fit after binding (global folding and formation of short-range intermolecular interactions).3

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p27 binds cyclin–CDK complexes through a sequential mechanism involving binding-induced protein folding

Cited by 282 publications

References 52 publications

p57Kip2 and Cancer: Time for a Critical Appraisal

p57Kip2 and Cancer: Time for a Critical Appraisal

Residual structure within the disordered C‐terminal segment of p21^{Waf1/Cip1/Sdi1} and its implications for molecular recognition

The binding mechanisms of intrinsically disordered proteins

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p27 binds cyclin–CDK complexes through a sequential mechanism involving binding-induced protein folding

Cited by 282 publications

References 52 publications

p57Kip2 and Cancer: Time for a Critical Appraisal

p57Kip2 and Cancer: Time for a Critical Appraisal

Residual structure within the disordered C‐terminal segment of p21Waf1/Cip1/Sdi1 and its implications for molecular recognition

The binding mechanisms of intrinsically disordered proteins

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Product

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Residual structure within the disordered C‐terminal segment of p21^{Waf1/Cip1/Sdi1} and its implications for molecular recognition