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

International Journal of Molecular Sciences

Xiaona Ji¹  Qiang Huang¹  Long Yu¹  Ruth Nussinov² 

[1] State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China; E-Mails:;Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA; E-Mail:

关键词: phosphorylation;    p53 protein;    p63;    p73;    protein binding site;    cancer;    intrinsically disordered proteins;   

DOI  :  10.3390/ijms150813275

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.