The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity

Authors

  • Andrei L Okorokov,

    Corresponding author
    1. Department of Pathology, Royal Free and University College Medical School, University College London, London, UK
    2. Wolfson Institute for Biomedical Research, University College London, London, UK
    • Corresponding authors: Department of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK. Tel.: +44 20 7631 6845; Fax: +44 20 7631 6803; E-mail: e.orlova@mail.cryst.bbk.ac.ukDepartment of Pathology, Royal Free and University College Medical School, University College London, London WCIE 6JJ, UK. Tel.: +44 20 7679 0959; Fax: +44 20 7388 4408; E-mail: a.okorokov@ucl.ac.uk

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  • Michael B Sherman,

    1. Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
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    • Present address: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1055, USA
  • Celia Plisson,

    1. School of Crystallography, Birkbeck College, London, UK
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  • Vera Grinkevich,

    1. Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden
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  • Kristmundur Sigmundsson,

    1. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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  • Galina Selivanova,

    1. Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden
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  • Jo Milner,

    1. YCR p53 Laboratory, Department of Biology, University of York, York, UK
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  • Elena V Orlova

    Corresponding author
    1. School of Crystallography, Birkbeck College, London, UK
    • Corresponding authors: Department of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK. Tel.: +44 20 7631 6845; Fax: +44 20 7631 6803; E-mail: e.orlova@mail.cryst.bbk.ac.ukDepartment of Pathology, Royal Free and University College Medical School, University College London, London WCIE 6JJ, UK. Tel.: +44 20 7679 0959; Fax: +44 20 7388 4408; E-mail: a.okorokov@ucl.ac.uk

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Abstract

p53 major tumour suppressor protein has presented a challenge for structural biology for two decades. The intact and complete p53 molecule has eluded previous attempts to obtain its structure, largely due to the intrinsic flexibility of the protein. Using ATP-stabilised p53, we have employed cryoelectron microscopy and single particle analysis to solve the first three-dimensional structure of the full-length p53 tetramer (resolution 13.7 Å). The p53 molecule is a D2 tetramer, resembling a hollow skewed cube with node-like vertices of two sizes. Four larger nodes accommodate central core domains, as was demonstrated by fitting of its X-ray structure. The p53 monomers are connected via their juxtaposed N- and C-termini within smaller N/C nodes to form dimers. The dimers form tetramers through the contacts between core nodes and N/C nodes. This structure revolutionises existing concepts of p53's molecular organisation and resolves conflicting data relating to its biochemical properties. This architecture of p53 in toto suggests novel mechanisms for structural plasticity, which enables the protein to bind variably spaced DNA target sequences, essential for p53 transactivation and tumour suppressor functions.

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