All tags p53 Isoforms and structure of p53

Isoforms and structure of p53

p53 has multiple isoforms and related family members and is active as a tetramer of 393 amino acids.

p53 Isoforms

There are multiple isoforms for p53 and the related p53 family members (p63 and p73), but their functional significance is unknown. They are produced by different promoter usage, alternative splicing, and alternative translation initiation sites.

It is thought that full-length p53 and its isoforms could interact to exert a level of control on the activity of p53.  There is evidence that differential ratios of isoforms could generate unique responses to stresses and influence oncogenesis in a distinctive manner. 

One study found that the expression of an N-terminally truncated p53 called p44 caused urinary bladder tumors, and variable expression of p53 isoforms has been observed in breast tumors compared to normal breast tissue (1).

p53 protein structure

The p53 protein is active as a tetramer of 4 chains of 393 amino acids. Each chain has several domains. At the N-terminal there are two distinct transactivation domains (TADI and TADII), a nuclear export signal (NES) followed by the proline rich domain (PD) and the DNA binding domain (DBD).

Then at the C-terminus there is an oligomerization domain (OD), three nuclear localization signals (NLS), a second NES and a lysine rich regulatory domain (RD).

The TADI (residues 1-42) and TADII (residues 43-62) are critical for p53’s regulation since they provide binding sites for the transcriptional machinery and the negative regulator MDM2 - they are differentially involved in the activation of a distinct set of p53 target genes.

The exact function of the PD (residues 63-97) is not well understood but the high proline frequency is conserved though species.

Additionally, from research using mouse models it is also known that the length of the PD is critical to maintain p53’s tumor suppressive function, and the domain also contains a common single nucleotide polymorphism (SNP) at codon 72 again highlighting the significance of this region.

The DBD (residues 102-292) is pivotal for the transcriptional activity of p53. It contains 4 of the 5 conserved boxes in p53. The OD (residues 323-356) allows p53 to form a tetramer which is organized as a dimer of dimers.

The C-terminus of p53 contains a cluster of three NLSs that mediate the nuclear location of the protein. These sequences bind to specific receptors and allow selective passage of p53 through the nuclear pore complex.

The C-terminal NES, a highly conserved region has been shown to be essential for nuclear export of p53. Both the NLS and NES regions are required for nuclear-cytosolic shuttling of p53 as a means to regulate p53 transcriptional function (2, 3).

Figure 1: p53 functional domains

References

  • 1. Levine AJ, Oren M. 2009. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 9(10):749-58. doi: 10.1038/nrc2723.    
  • 2. Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R. 2013. The MDM2-p53 pathway revisited. J Biomed Res. 27(4):254-71. doi: 10.7555/JBR.27.20130030.
  • 3. Meek DW, Anderson CW. 2009. Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol. 1(6):a000950. doi:10.1101/cshperspect.a000950.
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