Abstract
We have analyzed the folding pathway of the tetramerization domain of the tumor suppressor protein p53. Structures of transition states were determined from Φ–values for 25 mutations, including leucine to norvaline, and the analysis encompassed nearly every residue in the domain. Denatured monomers fold and dimerize, through a transition state with little native structure, to form a transient, highly structured dimeric intermediate. The intermediate dimerizes, through a native–like transition state with the primary dimers fully folded but with interdimer interactions only partially formed, to form the native tetramer as a 'dimer of dimers'.
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Acknowledgements
We gratefully acknowledge M. Bycroft, C. Johnson and J.L. Neira for scientific discussions and expert advice. This work was supported by the CRC of the UK. M.G.M. was supported by a grant from the European Union.
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Mateu, M., Sánchez Del Pino, M. & Fersht, A. Mechanism of folding and assembly of a small tetrameric protein domain from tumor suppressor p53. Nat Struct Mol Biol 6, 191–198 (1999). https://doi.org/10.1038/5880
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DOI: https://doi.org/10.1038/5880
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