Structural Basis for p300 Taz2-p53 TAD1 Binding and Modulation by Phosphorylation

Feng, Hanqiao; Jenkins, Lisa M. Miller; Durell, Stewart R.; Hayashi, Ryo; Mazur, Sharlyn J.; Cherry, Scott; Tropea, Joseph E.; Miller, Maria; Wlodawer, Alexander; Appella, Ettore; Bai, Yawen

doi:10.1016/j.str.2008.12.009

Cited by 129 publications

(192 citation statements)

References 53 publications

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“…5a), explaining the moderately decreased binding affinity of the Taz2 R1731A mutant protein. On the other hand, mutation of Arg1737 to Ala would remove the unfavorable hydrophilic environment for Leu25 of p53 and should increase the binding affinity, which is in agreement with previous results (Feng et al, 2009).…”

Section: Implications Fortaz2 Ligand Bindingsupporting

confidence: 92%

“…NMR titration showed a sevenfold and 11-fold increase in affinity for Taz2 upon monophosphorylation at Ser15 and Thr18, respectively. Interestingly, only a sevenfold increase was generated upon diphosphorylation at these sites (Feng et al, 2009). Several findings pointed towards the possibility of two distinct modes of interaction with Taz2 for phosphorylated and unphosphorylated forms of p53-TAD1.…”

Section: Implications Fortaz2 Ligand Bindingmentioning

confidence: 99%

“…The interaction surface for binding of protein ligands revealed by the structures of the Taz2 domain complexed with p53-TAD1 (Feng et al, 2009) and with STAT1-TAD (Wojciak et al, 2009) is shown in Fig. 5.…”

Section: Implications Fortaz2 Ligand Bindingmentioning

confidence: 99%

“…As is the case with STAT1-TAD, this second amphipathic sequence within p53-TAD is preceded by negatively charged amino acids and its affinity of interaction with Taz2 is not affected by phosphorylation . Evidence for overlapping binding sites for p53 TAD1 and TAD2 peptides was provided by 1 H-15 NHSQC titration experiments on 15 N-labeled Taz2 (Feng et al, 2009). Two binding motifs from p53 TAD are separated by a 20-residue flexible linker.…”

Section: Implications Fortaz2 Ligand Bindingmentioning

confidence: 99%

“…The mechanism of this specific recognition and stimulusdependent selectivity is poorly understood. Three-dimensional structures have been determined by NMR for unliganded CBP-Taz2 (De Guzman et al, 2000) and its complexes with peptides derived from the TAD of STAT1 (Wojciak et al, 2009) and from the conserved region 1 (CR1) domain of the adenoviral oncoprotein E1A , as well as for the p300-Taz2-p53-TAD1 complex (Feng et al, 2009). Both STAT1-TAD and p53-TAD1 form short helices upon binding and interact with the Taz2 domain through an extended interface.…”

Section: Introductionmentioning

confidence: 99%

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Structure of the Taz2 domain of p300: insights into ligand binding

Miller

Dauter

Cherry³

et al. 2009

Acta Crystallogr D Biol Crystallogr

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CBP and its paralog p300 are histone acetyl transferases that regulate gene expression by interacting with multiple transcription factors via specialized domains. The structure of a segment of human p300 protein (residues 1723-1836) corresponding to the extended zinc-binding Taz2 domain has been investigated. The crystal structure was solved by the SAD approach utilizing the anomalous diffraction signal of the bound Zn ions. The structure comprises an atypical helical bundle stabilized by three Zn ions and closely resembles the solution structures determined previously for shorter peptides. Residues 1813-1834 from the current construct form a helical extension of the C-terminal helix and make extensive crystalcontact interactions with the peptide-binding site of Taz2, providing additional insights into the mechanism of the recognition of diverse transactivation domains (TADs) by Taz2. On the basis of these results and molecular modeling, a hypothetical model of the binding of phosphorylated p53 TAD1 to Taz2 has been proposed.

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Section: Implications Fortaz2 Ligand Bindingsupporting

confidence: 92%

Section: Implications Fortaz2 Ligand Bindingmentioning

confidence: 99%

Section: Implications Fortaz2 Ligand Bindingmentioning

confidence: 99%

Section: Implications Fortaz2 Ligand Bindingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure of the Taz2 domain of p300: insights into ligand binding

Miller

Dauter

Cherry³

et al. 2009

Acta Crystallogr D Biol Crystallogr

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Tumor‐Suppressor p53TAD^1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach

et al. 2020

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Conformationally flexible protein complexes represent a major challenge for structural and dynamical studies. We present herein a method based on a hybrid NMR/MD approach to characterize the complex formed between the disordered p53TAD 1-60 and the metastasis-associated S100A4. Disorder-toorder transitions of both TAD1 and TAD2 subdomains upon interaction is detected. Still, p53TAD 1-60 remains highly flexible in the bound form, with residues L26, M40, and W53 being anchored to identical hydrophobic pockets of the S100A4 monomer chains. In the resulting "fuzzy" complex, the clamplike binding of p53TAD 1-60 relies on specific hydrophobic anchors and on the existence of extended flexible segments. Our results demonstrate that structural and dynamical NMR parameters (cumulative Δδ, SSP, temperature coefficients, relaxation time, hetNOE) combined with MD simulations can be used to build a structural model even if, due to high flexibility, the classical solution structure calculation is not possible.

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Molecular basis of the interactions between the disordered Neh4 and Neh5 domains of Nrf2 and CBP/p300 in oxidative stress response

Karunatilleke,

Brickenden,

Choy

2024

Protein Science

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Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a major transcription factor that functions in maintaining redox homeostasis in cells. It mediates the transcription of cytoprotective genes in response to environmental and endogenous stresses to prevent oxidative damage. Thus, Nrf2 plays a significant role in chemoprevention. However, aberrant activation of Nrf2 has been shown to protect cancer cells from apoptosis and contribute to their chemoresistance. The interaction between Nrf2 and CBP is critical for the gene transcription activation. CBP and its homologue p300 interact with two transactivation domains in Nrf2, Neh4, and Neh5 domains through their TAZ1 and TAZ2 domains. To date, the molecular basis of this crucial interaction is not known, hindering a more detailed understanding of the regulation of Nrf2. To close this knowledge gap, we have used a set of biophysical experiments to dissect the Nrf2‐CBP/p300 interactions. Structural properties of Neh4 and Neh5 and their binding with the TAZ1 and TAZ2 domains of CBP/p300 were characterized. Our results show that the Neh4 and Neh5 domains of Nrf2 are intrinsically disordered, and they both can bind the TAZ1 and TAZ2 domains of CBP/p300 with micromolar affinities. The findings provide molecular insight into the regulation of Nrf2 by CBP/p300 through multi‐domain interactions.

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Structural Basis for p300 Taz2-p53 TAD1 Binding and Modulation by Phosphorylation

Cited by 129 publications

References 53 publications

Structure of the Taz2 domain of p300: insights into ligand binding

Structure of the Taz2 domain of p300: insights into ligand binding

Tumor‐Suppressor p53TAD^1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach

Molecular basis of the interactions between the disordered Neh4 and Neh5 domains of Nrf2 and CBP/p300 in oxidative stress response

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Structural Basis for p300 Taz2-p53 TAD1 Binding and Modulation by Phosphorylation

Cited by 129 publications

References 53 publications

Structure of the Taz2 domain of p300: insights into ligand binding

Structure of the Taz2 domain of p300: insights into ligand binding

Tumor‐Suppressor p53TAD1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach

Molecular basis of the interactions between the disordered Neh4 and Neh5 domains of Nrf2 and CBP/p300 in oxidative stress response

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Tumor‐Suppressor p53TAD^1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach