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Open Access Publications from the University of California

Structural characterization of the C-terminal domains in the p53 protein family

  • Author(s): Ou, Horng Der
  • Advisor(s): Minor, Jr, Daniel L
  • et al.

The identification of many homologs and paralogs of the most famous tumor suppressor, p53, has expanded its role from tumor suppression to epidermal development, neuronal development, and protection of germ cells. Of all the members in the p53 protein family, the DNA binding domain (DBD) is the most conserved domain. In contrast, the C-terminal region is diverse in sequence and composition of protein domains that include the oligomerization domain (OD), the sterile alpha motif (SAM) domain, and the transcription inhibitory domain (TID). While the function of each domain has been delineated, the SAM domain is the least functionally characterized, yet it is conserved between vertebrate and invertebrate p53. Furthermore, mutations of this domain in p63, a homolog of p53, cause defects in epidermal development in human.

The diversity of the C-terminus is most apparent in two p53 like proteins in C. elegans (CEP-1) and Drosophila (Dmp53). Neither of these proteins have any domains in the C-terminus found in other p53 protein family members, yet the DBD in both proteins recognize the DNA consensus motif in vitro. Interestingly, CEP-1 and Dmp53 could only elicit an apoptotic response, but not both cell cycle arrest and apoptosis like in human. The variation of the C-terminal end by each member of the p53 protein family may account for the discrepancy between identical in vitro DNA specificity, and distinct promoter specificity in vivo.

By using bioinformatics and structural determination by nuclear magnetic resonance, the domain architecture of the C-termini of CEP-1 and Dmp53 was revealed. In CEP-1, an OD and a SAM domain were identified, in which the stability of the OD depends on its interaction with the SAM domain, thus suggesting an early function for the SAM domain. In Dmp53, the OD displays an unconventional fold that requires an additional helix to stabilize the OD. Structural and biochemical investigations into the human SAM domain in p63 also reveal that the SAM domain has interactions with the OD. Mutations in the SAM domain may disrupt this interaction and cause a change in the conformation of p63 that results in its abnormal function.

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