Molecular basis of the interactions between the p73 N terminus and p300: Effects on transactivation and modulation by phosphorylation

Burge, Sarah; Teufel, Daniel P.; Townsley, Fiona M.; Freund, Stefan; Bycroft, Mark; Fersht, Alan R.

doi:10.1073/pnas.0900383106

Cited by 32 publications

(52 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results have been found for the N-terminal binding of four different p300 domains and MDM2. 31,43 This is in agreement with mice knockout data in vivo suggesting that N-terminal phosphorylation is more likely to be a fine-tuning regulatory system of p53. 3 Nevertheless, the small differences in affinity change might still be physiologically relevant.…”

Section: Discussionsupporting

confidence: 87%

Posttranslational Modifications Affect the Interaction of S100 Proteins with Tumor Suppressor p53

Dieck

Teufel

Jaulent

et al. 2009

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 87%

Posttranslational Modifications Affect the Interaction of S100 Proteins with Tumor Suppressor p53

Dieck

Teufel

Jaulent

et al. 2009

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

“…In contrast, phosphorylation of Thr14 in p73TAD was shown to increase the affinity to p300 Taz2 domain by 10-fold. 38 Therefore, similar to the situation in p53TAD, phosphorylation of p73TAD may modulate the helical stability to regulate interactions with binding partners. However, such binding modulation by phosphorylation would be impossible for p63TAD because the corresponding phosphorylation site in the FxxWFxxL motif is replaced with a valine (Val54).…”

Section: Discussionmentioning

confidence: 91%

Structural convergence of unstructured p53 family transactivation domains in MDM2 recognition

Shin

Lee

et al. 2015

Cell Cycle

View full text Add to dashboard Cite

The p53, p63, and p73 proteins belong to the p53 family of transcription factors, which play key roles in tumor suppression. Although the transactivation domains (TADs) of the p53 family are intrinsically disordered, these domains are commonly involved in the regulatory interactions with mouse double minute 2 (MDM2). In this study, we determined the solution structure of the p73TAD peptide in complex with MDM2 using NMR spectroscopy and biophysically characterized the interactions between the p53 family TAD peptides and MDM2. In combination with mutagenesis data, the complex structures revealed remarkably close mimicry of the MDM2 recognition mechanism among the p53 family TADs. Upon binding with MDM2, the intrinsically disordered p73TAD and p63TAD peptides adopt an amphipathic a-helical conformation, which is similar to the conformation of p53TAD, although the a-helical content induced by MDM2 binding varies. With isothermal titration calorimetry (ITC) and circular dichroism (CD) data, our biophysical characterization showed that p73TAD resembles p53TAD more closely than p63TAD in terms of helical stability, MDM2 binding affinity, and phosphorylation effects on MDM2 binding. Therefore, our structural information may be useful in establishing alternative anticancer strategies that exploit the activation of the p73 pathway against human tumors bearing p53 mutations.

show abstract

“…NCBD is responsible for the interaction of CBP with a number of other important proteins such as the steroid receptor coactivators (10), p53 (11), p73 (12), the interferon regulatory proteins (IRF) 3 and 7 (13,14) and the viral protein Tax (15). In the ligand-free state, the NCBD is compact and has a high degree of helicity, but apparently it lacks sigmoidicity in the unfolding curve (16)(17)(18).…”

Section: Creb Binding Protein | Folding Upon Binding | Nmr Spectroscopymentioning

confidence: 99%

Conformational selection in the molten globule state of the nuclear coactivator binding domain of CBP

Kjærgaard

Teilum

Poulsen

2010

Proc. Natl. Acad. Sci. U.S.A.

153

242

View full text Add to dashboard Cite

Native molten globules are the most folded kind of intrinsically disordered proteins. Little is known about the mechanism by which native molten globules bind to their cognate ligands to form fully folded complexes. The nuclear coactivator binding domain (NCBD) of CREB binding protein is particularly interesting in this respect as structural studies of its complexes have shown that NCBD folds into two remarkably different states depending on the ligand being ACTR or IRF-3. The ligand-free state of NCBD was characterized in order to understand the mechanism of folding upon ligand binding. Biophysical studies show that despite the molten globule nature of the domain, it contains a small cooperatively folded core. By NMR spectroscopy, we have demonstrated that the folded core of NCBD has a well ordered conformer with specific side chain packing. This conformer resembles the structure of the NCBD in complex with the protein ligand, ACTR, suggesting that ACTR binds to prefolded NCBD molecules from the ensemble of interconverting structures.CREB binding protein | folding upon binding | NMR spectroscopy T he protein structure-function paradigm has dominated structural and molecular biology over the past five decades. This paradigm has been challenged by the discovery of functional but intrinsically disordered proteins (IDPs) (1). IDPs are abundant in higher organisms and are necessary for many crucial biological functions such as cell cycle regulation, signal transduction, and regulation of transcription (2, 3). Structural studies of IDPs have shown that despite the high degree of disorder, these proteins are far from randomly structured and form transient, yet specific, secondary and tertiary structural elements (4, 5). The success of the structure-function paradigm in explaining the function of folded proteins suggests that the functions of the IDPs may also be understood by studying the transient structure of the disordered state.The molten globule was originally discovered as a partially folded state under mildly denaturing conditions and was shown to accumulate as an intermediate during protein folding reactions (6, 7). With the emergence of the IDPs, proteins were discovered where the molten globule is the functionally active state. Native molten globules are the most compact conformational state considered as IDPs (4). Molten globules have native-like secondary structure, but are believed to lack the well-defined tertiary interactions found in folded proteins. Most high resolution NMR studies of the molten globule state have focused on the secondary structure of the backbone as this is more readily accessible from secondary chemical shifts (8). The degree of side chain packing, however, is less well understood. Molten globules are believed to have dynamic hydrophobic cores due to the lack of signal in the near-UV CD spectrum and the broadening of NMR signals of aromatic groups (6, 7). Recent studies have shown that the side chains in the α-lactalbumin molten globule exchange between several well defined confor...

show abstract

Molecular basis of the interactions between the p73 N terminus and p300: Effects on transactivation and modulation by phosphorylation

Cited by 32 publications

References 42 publications

Posttranslational Modifications Affect the Interaction of S100 Proteins with Tumor Suppressor p53

Posttranslational Modifications Affect the Interaction of S100 Proteins with Tumor Suppressor p53

Structural convergence of unstructured p53 family transactivation domains in MDM2 recognition

Conformational selection in the molten globule state of the nuclear coactivator binding domain of CBP

Contact Info

Product

Resources

About