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The structures of full-length p53 monomer and tetramer when unbound to DNA and structural domain determination in p53


p53 is well-known as a tumor suppressor or genome guardian. It is a transcription factor composed of multiple domains. When bound to DNA, p53 assembles as a tetramer and starts recruiting other proteins to form a transactivation complex that initiates the transcription of p53-targeted genes. Due to p53's inherent flexibility in its N and C termini, the structure of full-length p53 has not been solved by X-ray crystallography. However, structures of fragments of p53 domains have been solved by X-ray crystallography. Electron microscopy (EM) single particle 3D reconstruction is an alternative way of solving p53's structure. In this thesis work, I have determined the structure of full-length p53 as a monomer and as a tetramer using EM single particle 3D reconstruction. p53 monomer, with a molecular weight of 43kDa, is one of the smallest proteins that have been solved by EM. The EM structure of p53 monomer looks like a sickle-shaped molecule where the N-terminus and C-terminus form a right angle, which is in agreement with existing crystallographic data. p53 tetramer, with a molecular weight of 172 kDa, has a square shape where the DNA- binding domains are not in contact and the tetrameric structure is maintained by interactions involving the N- and C-terminal domains. Based on this tetrameric structure and known structures of p53 fragments in X-ray crystallography, I have come to the conclusion that there are two distinct quaternary states of p53 tetramers, one unbound to DNA and the other bound to DNA. When unbound to DNA, p53 tetramer has an open, relaxed square shape which is larger than the compacted parallelogram shape of p53 tetramer when bound to DNA. p53 mutants often observed in cancer, which are being investigated in my lab at the moment, are speculated to accumulate inside the nucleus in this open, relaxed quaternary state

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