p53, the Cellular Gatekeeper for Growth and Division

As the tale of p53 unfolds, it becomes ever more intriguing. Although our understanding of the critical and complex roles played by p53 is progressing rapidly, new findings continue to pose new paradoxes. Here we present some of these recent advances in p53 research and discuss how they either shed light on or add to the complexities of p53. Therefore, we only briefly summarize some of the key developments leading to our current state of knowledge. For further information, the reader is referred to several excellent reviews that have focused on p53 research (see Donehower and Bradley 1993; Levine 1993; Greenblatt et al. 1994; Oren 1994; Prives 1994; Kinzler and Vogelstein 1996).

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p53: puzzle and paradigm.

The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic alpha helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 alpha helix and, in particular, on a triad of p53 amino acids-Phe19, Trp23, and Leu26-which insert deep into the MDM2 cleft. These same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic alpha helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.

https://science.sciencemag.org/content/sci/274/5289/948.full.pdf

Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.

Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

Zinc ions are key structural components of a large number of proteins. The binding of zinc stabilizes the folded conformations of domains so that they may facilitate interactions between the proteins and other macromolecules such as DNA. The modular nature of some of these zinc-containing proteins has allowed the rational design of site-specific DNA binding proteins. The ability of zinc to be bound specifically within a range of tetrahedral sites appears to be responsible for the evolution of the side range of zinc-stabilized structural domains now known to exist. The lack of redox activity for the zinc ion and its binding and exchange kinetics also may be important in the use of zinc for specific functional roles.

https://science.sciencemag.org/content/sci/271/5252/1081.full.pdf

The Galvanization of Biology: A Growing Appreciation for the Roles of Zinc

Mutations in the p53 tumor suppressor are the most frequently observed genetic alterations in human cancer. The majority of the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues 102-292), and they result in loss of DNA binding. The crystal structure of a complex containing the core domain of human p53 and a DNA binding site has been determined at 2.2 angstroms resolution and refined to a crystallographic R factor of 20.5 percent. The core domain structure consists of a beta sandwich that serves as a scaffold for two large loops and a loop-sheet-helix motif. The two loops, which are held together in part by a tetrahedrally coordinated zinc atom, and the loop-sheet-helix motif form the DNA binding surface of p53. Residues from the loop-sheet-helix motif interact in the major groove of the DNA, while an arginine from one of the two large loops interacts in the minor groove. The loops and the loop-sheet-helix motif consist of the conserved regions of the core domain and contain the majority of the p53 mutations identified in tumors. The structure supports the hypothesis that DNA binding is critical for the biological activity of p53, and provides a framework for understanding how mutations inactivate it.

https://science.sciencemag.org/content/sci/265/5170/346.full.pdf

Yunje Cho

Papers

Crystal structure of a p53 tumor suppressor-DNA complex: Understanding tumorigenic mutations