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Published: Jul 27, 2015 11:56:12 AM
Published: Jul 20, 2015 3:05:08 PM
Published: Jul 15, 2015 4:18:43 PM
The p53 suppressor protein is a classic gatekeeper of cellular fate. In its normal latent form, p53 has low affinity for its specific DNA sequences, but acquires high-affinity binding in response to genotoxic stress, thus adopting the active form. Once activated, p53 initiates cell cycle arrest, senescence or apoptosis via pathways involving transactivation of p53 target genes. In addition, a number of reports link p53 to DNA repair processes. However, the exact molecular mechanism(s) of p53 activation as a transcription factor and/or participant in DNA repair pathways remains unknown.
p53 major tumour suppressor protein has presented a challenge for structural biology for two decades. 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 13.7Ǻ). 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.
Figure 1. Schematic representation of p53 dimers and tetramer architecture. Atomic structures of p53 domains docked into the 3D map (EMD-1141). Two p53 dimers shown in blue and red.
Okorokov AL, Orlova EV. (2009) Structural biology of the p53 tumour suppressor. Curr. Opin. Struct. Biol. 19:1-6.
Okorokov AL, Sherman MB, Plisson C, Grinkevich V, Sigmundsson K, Selivanova G, Milner J, Orlova EV. (2006) The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity. EMBO Journal 25:5191-5200. free access