Structural Biochemistry/P63

p63, also known as TP63 (tumor protein p63), is encoded by the TP63 gene. It is also part of the p53 family along with p53 and p73. It was discovered in 1998 as a p53-related ortholog in mouse and human cells. Similarly to p53 and p73, p63 also has domains that are highly conserved across the family. Because of this homology, it is believed that the three genes in the p53 family have the same functions. However, after studying the genes more specifically and carefully, it was been shown that even though the genes may performs some of the same functions, they each have unique physiological roles. p63 has been associated more with have a developmental role rather than a tumor suppressing role. All three genes can cause cell cycle arrest and apoptosis, but like p73, there is alternative splicing for p63 that produces different isoforms of p63. α forms contain the sterile alpha motif (SAM) that is responsible for mediating protein-protein interactions.

Structure

C-terminal domain of the p63 protein PDB rendering based on 1rg6.

The structure of p63 seems to be more similar to the structure of p73 than to p53. p63 has a long transactivation domain (TA), a DNA binding domain (DBD) and an oligomerization domain (OD) that are all highly conserved with the corresponding domains in p53 and p73. The protein is composed of 15 exons and various isoforms of protein exist. Isoforms containing the long transactivation domain as known as TA forms and are the full-length protein TAp63, while isoforms that do have only the short (~15-18 amino acid residues) transactivation domain are called ΔN forms, ΔNp63. Each form can undergo alternative splicing that produces three different C-termini forms, α, β, or γ Additionally, both TAp63α and ΔNp63α also have a sterile alpha motif (SAM) interacting domain at its C-terminus that is responsible for mediating protein-protein interactions. The ΔNp63 isoform of p63 (like the ΔNp73 isoform of p73) does have only the short N-terminal TA domain and this p63 isoform seems to be the main negative inhibitors of TAp63 isoforms as well as other family members of the p53 family, similar to role of the ΔNp73 isoform.