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Wild-type p53 adopts a 'mutant'-like conformation when bound to DNA
T D Halazonetis1, L J Davis, A N Kandil
1Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486.
Abstract:
p53 is a negative regulator of cell growth. The majority of human tumors express mutant p53 proteins, which can be distinguished from wild-type by their immuno-reactivity to a panel of conformation-specific monoclonal antibodies, such as PAb421, PAb1620 and PAb246. Wild-type p53 has sequence-specific DNA binding activity. We demonstrate that upon binding DNA wild-type p53 changes conformation at both its N- and C-termini, such that it adopts a 'mutant'-like conformation. Very few of the known DNA binding proteins exhibit long-range conformational changes upon binding to DNA. Such proteins, like the Drosophila heat shock transcription factor, have DNA binding domains whose activity is regulated by conformation. The DNA binding activity, and therefore the function, of wild-type p53 may be regulated via its ability to adopt distinct conformations.
Insights
Wild-type p53 protein changes conformation upon DNA binding, adopting a mutant-like structure. This conformational change may regulate the DNA binding activity and function of wild-type p53.
Area of Science:
- Molecular Biology
- Cancer Research
- Protein Conformation
Background:
- p53 acts as a negative regulator of cell growth.
- Mutant p53 proteins are prevalent in human tumors and exhibit distinct immunoreactivity compared to wild-type p53.
- Wild-type p53 possesses sequence-specific DNA binding activity.
Purpose of the Study:
- To investigate the conformational changes of wild-type p53 upon DNA binding.
- To explore the potential regulatory mechanism of wild-type p53 function through conformational alterations.
Main Methods:
- Utilized conformation-specific monoclonal antibodies (e.g., PAb421, PAb1620, PAb246) to distinguish between wild-type and mutant p53.
- Demonstrated changes in wild-type p53 conformation at both N- and C-termini upon DNA interaction.
Main Results:
- Wild-type p53 undergoes a significant conformational change when binding to DNA.
- This induced conformation resembles that of 'mutant'-like p53.
- Such long-range conformational changes upon DNA binding are rare among DNA-binding proteins.
Conclusions:
- Wild-type p53's DNA binding activity and overall function may be modulated by its ability to adopt distinct conformations.
- This conformational plasticity offers a novel regulatory mechanism for p53 function in cellular processes.