Comparison of p53 Structure:Wild type vs. mutant What change in wild type p53 may lead to cancer?
Structure of Wild-type p53 1olg 1tup Figure from Protein Data Bank 1ycq
Structural Domains of p53 • Composed of 4 polypeptide chains • Each chain has 3 domains • Tetramerization domain named 1olg • DNA binding domain named 1tup • Activation domain named 1ycg
Structure of DNA Binding domain is highly conserved (purple) Figure from ConSurf
Same molecule (1tup) as ribbon diagram Figure from ConSurf
Notice that the portion of the protein that directly interacts with the DNA is highly conserved (purple) • Other protein regions are less highly conserved
One amino acid substitution from a mutant p53 Figure from ConSurf
Protein Alignment of Wild-type p53 vs. mutant p53 • LRVEYLDDRNTFRHSVVVPYEPPEVGSD • LRVEYLDDRNTFRHSVVVPYEPPEVGSE • Summary: Amino acid substitution DE is from aspartate to glutatmate (both are negatively charged)
Summary • Mutations involving amino acids substitutions in conserved domains can negatively affect function of p53.
Future Work • Identify the specific amino acid locations in the 1tup and determine if the mutations are in the highly conserved region and indicate these on our figures