Peptide-Protein Interactions Suggest That Acetylation of Lysines 381 and 382 of p53 Is Important for Positive Coactivator 4-p53 Interaction

Subrata Debnath; Snehajyoti Chatterjee; Mohammed Arif; Tapas K. Kundu; Siddhartha Roy

doi:10.1074/jbc.M110.205328

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Peptide-Protein Interactions Suggest That Acetylation of Lysines 381 and 382 of p53 Is Important for Positive Coactivator 4-p53 Interaction

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Peptide-Protein Interactions Suggest That Acetylation of Lysines 381 and 382 of p53 Is Important for Positive Coactivator 4-p53 Interaction

Subrata Debnath, Snehajyoti Chatterjee, Mohammed Arif, Tapas K. Kundu and Siddhartha Roy

The Journal of biological chemistry, Vol.286(28), pp.25076-25087

05/17/2011

DOI: 10.1074/jbc.M110.205328

PMCID: PMC3137081

PMID: 21586571

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Abstract

The human transcriptional positive coactivator 4 (PC4) activates several p53-dependent genes. It has been demonstrated that this is a consequence of direct interaction with p53. Previously, we have concluded that PC4 interacts mainly with the C-terminal negative regulatory domain of p53 through its DNA binding C-terminal half. NMR chemical shift perturbation studies with peptide fragments indicated that amino acids 380–386 of p53 are crucial for interaction with PC4. This was verified by fluorescence anisotropy and sedimentation velocity studies. A peptide consisting of p53-(380–386) sequence, when attached to a cell penetration tag and nuclear localization signal, localizes to the nucleus and inhibits luciferase gene expression from a transfected plasmid carrying a Luc gene under a p53-dependent promoter. Acetylation of lysine 382/381 enhanced the binding of this peptide to PC4 by about an order of magnitude. NMR and mutagenesis studies indicated that serine 73 of PC4 is an important residue for recognition of p53. Intermolecular nuclear Overhauser effect placed aspartate 76 in the vicinity of lysine 381, indicating that the region around residues 73–76 of PC4 is important for p53 recognition. We conclude that the 380–386 region of p53 interacts with the region around residues 73–76 of PC4, and acetylation of lysine 382/381 of p53 may play an important role in modulating p53-PC4 interaction and as a consequence PC4 mediated activation of p53 target genes.

Fluorescence

Gene Regulation

NMR

Protein-Protein Interactions

Transcription

Transcription Coactivators

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Title: Subtitle: Peptide-Protein Interactions Suggest That Acetylation of Lysines 381 and 382 of p53 Is Important for Positive Coactivator 4-p53 Interaction
Creators: Subrata Debnath - Indian Institute of Chemical Biology
Snehajyoti Chatterjee - Jawaharlal Nehru Centre for Advanced Scientific Research
Mohammed Arif - Jawaharlal Nehru Centre for Advanced Scientific Research
Tapas K. Kundu - Jawaharlal Nehru Centre for Advanced Scientific Research
Siddhartha Roy - From the Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research (India), 4, Raja S. C. Mullick Road, Kolkata 700032 and
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.286(28), pp.25076-25087
DOI: 10.1074/jbc.M110.205328
PMID: 21586571
PMCID: PMC3137081
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology
Alternative title: Acetylation of p53 Enhances Interaction with PC4
Language: English
Date published: 05/17/2011
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984303748302771

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