Next Article in Journal
Comparative Evaluation of Urinary PCA3 and TMPRSS2: ERG Scores and Serum PHI in Predicting Prostate Cancer Aggressiveness
Next Article in Special Issue
Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers
Previous Article in Journal
The First Mutation Identified in a Chinese Acrodysostosis Patient Confirms a p.G289E Variation of PRKAR1A Causes Acrodysostosis
Previous Article in Special Issue
Effects of β2-Adrenergic Receptor Gene Polymorphisms on Ritodrine Therapy in Pregnant Women with Preterm Labor: Prospective Follow-Up Study
Article Menu
Issue 8 (August) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2014, 15(8), 13275-13298; doi:10.3390/ijms150813275

Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs

1
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China
2
Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA
3
Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
*
Authors to whom correspondence should be addressed.
Received: 10 June 2014 / Revised: 23 July 2014 / Accepted: 24 July 2014 / Published: 29 July 2014
(This article belongs to the Collection Human Single Nucleotide Polymorphisms and Disease Diagnostics)
View Full-Text   |   Download PDF [4027 KB, uploaded 29 July 2014]   |  

Abstract

p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated in human cancer, using a bioinformatics approaches, we examined the phosphorylation site and its nearby flanking residues, focusing on the consensus phosphorylation motif pattern, amino-acid correlations within the phosphorylation motifs, the propensity of structural disorder of the phosphorylation motifs, and cancer mutations observed within the phosphorylation motifs. Many p53 phosphorylation sites are targets for several kinases. The phosphorylation sites match 17 consensus sequence motifs out of the 29 classified. In addition to proline, which is common in kinase specificity-determining sites, we found high propensity of acidic residues to be adjacent to phosphorylation sites. Analysis of human cancer mutations in the phosphorylation motifs revealed that motifs with adjacent acidic residues generally have fewer mutations, in contrast to phosphorylation sites near proline residues. p53 phosphorylation motifs are mostly disordered. However, human cancer mutations within phosphorylation motifs tend to decrease the disorder propensity. Our results suggest that combination of acidic residues Asp and Glu with phosphorylation sites provide charge redundancy which may safe guard against loss-of-function mutations, and that the natively disordered nature of p53 phosphorylation motifs may help reduce mutational damage. Our results further suggest that engineering acidic amino acids adjacent to potential phosphorylation sites could be a p53 gene therapy strategy. View Full-Text
Keywords: phosphorylation; p53 protein; p63; p73; protein binding site; cancer; intrinsically disordered proteins phosphorylation; p53 protein; p63; p73; protein binding site; cancer; intrinsically disordered proteins
Figures

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Ji, X.; Huang, Q.; Yu, L.; Nussinov, R.; Ma, B. Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs. Int. J. Mol. Sci. 2014, 15, 13275-13298.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top