Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein.
TP53 encodes p53, which is a nuclear phosphoprotein with cancer-inhibiting properties. In response to DNA damage, p53 is activated and mediates a set of antiproliferative responses including cell-cycle arrest and apoptosis. Mutations in the TP53 gene are associated with more than 50% of human cancers, and 90% of these affect p53-DNA interactions, resulting in a partial or complete loss of transactivation functions. These mutations affect the structural integrity and/or p53-DNA interactions, leading to the partial or complete loss of the protein's function. We report here the results of a systematic automated analysis of the effects of p53 mutations on the structure of the core domain of the protein. We found that 304 of the 882 (34.4%) distinct mutations reported in the core domain can be explained in structural terms by their predicted effects on protein folding or on protein-DNA contacts. The proportion of "explained" mutations increased to 55.6% when substitutions of evolutionary conserved amino acids were included. The automated method of structural analysis developed here may be applied to other frequently mutated gene mutations such as dystrophin, BRCA1, and G6PD.
Martin
Andrew C R
AC
School of Animal and Microbial Sciences, University of Reading, Reading, UK.
Facchiano
Angelo M
AM
Cuff
Alison L
AL
Hernandez-Boussard
Tina
T
Olivier
Magali
M
Hainaut
Pierre
P
Thornton
Janet M
JM
D019943:Amino Acid Substitution / Q000235:genetics; D001331:Automation; D017124:Conserved Sequence / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D030561:Databases, Nucleic Acid; D016158:Genes, p53 / Q000235:genetics*; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011392:Proline / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D004247:DNA; D011392:Proline; D015032:Zinc; D005998:Glycine