Abstract
Tumor suppressors p53, p63 and p73 comprise a family of stress-responsive transcription factors with distinct functions in development and tumor suppression. Most human cancers lose p53 function, yet all three proteins are capable of inducing apoptosis or cellular senescence. Mechanisms are therefore under investigation to activate p73-dependent apoptosis in p53-deficient cancer cells. Significantly, the DNA-binding domain (DBD) of p73 escapes viral oncoproteins and displays an enhanced thermal stability. To further understand the variant features of p73, we solved the high‐resolution crystal structure of the p73 DBD as well as its complex with the ankyrin repeat and SH3 domains of the pro-apoptotic factor ASPP2. The p73 structure exhibits the same conserved architecture as p53 but displays a divergent L2 loop, a known site of protein–protein interaction. The loop in p73 is changed by a two-residue insertion that also induces repacking around the site of the p53 mutational hotspot R175. Importantly, the binding of ASPP2 is preserved by conformational changes in both the ankyrin repeat and SH3 domains. These results further highlight the structural variation that impacts p53 family interactions within the p53 interactome.
Highlights
The p53 family of transcription factors comprises p53 and the paralogs p63 and p73.1 Under conditions of cellular stress, all three proteins are activated to induce genes necessary for cell cycle arrest or apoptosis.[2]
The p53 family DNA-binding domain (DBD) has undergone considerable structural evolution, as evidenced by the distinct structure of the earliest known orthologue, Caenorhabditis elegans Cep-1.32 An important finding from the structure determination of the human p73 DBD is the apparent lack of structural evolution following the expansion of the ancestral p53 gene into the three family members p53, p63 and p73
The C-terminal oligomerization domain (OD) has evolved structural mechanisms that restrict p53 assembly with p63 and p73.33–35 The conservation of the DBD fold in humans is consistent with the similar consensus DNA response elements determined for p53, p63 and p73.36,37 Together, these data highlight the overriding importance of DNA binding to p53 family activities
Summary
The p53 family of transcription factors comprises p53 and the paralogs p63 and p73.1 Under conditions of cellular stress, all three proteins are activated to induce genes necessary for cell cycle arrest or apoptosis.[2]. While inactivation of p53 is a common event in human cancers, it is rare for p63 or Abbreviations used: DBD, DNA-binding domain; OD, oligomerization domain; TEV, tobacco etch virus; TCEP, tris(2-carboxyethyl)phosphine; PDB, Protein Data Bank; TLS, translation/liberation/screw. All three proteins share a similar domain organization containing an N-terminal transactivation domain, a DNA-binding domain (DBD) and a Cterminal oligomerization domain (OD).[9] p63 and p73 contain an additional sterile α-motif domain and an inhibitory domain at the C-terminus. Both p63 and p73 share approximately 60% sequence identity with p53 in the DBD, and DNA contact residues are strictly conserved across all three proteins.[9]
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