Structural insight into the interaction between p53 TAD1 and AIMP2-DX2 by NMR

p53 is the most studied tumor suppressor and a key transcriptional factor, with discrete domains that regulate cellular pathways such as apoptosis, angiogenesis, cell-cycle arrest, DNA repair, and senescence. Previous studies have suggested that AIMP2, and ARS-interacting multifunctional protein 2, promote cell death via the protective interaction with p53 upon DNA damage. Also, oncogenic splicing variant of AIMP2 lacking exon2, AIMP2-DX2, compromises the pro-apoptotic activity and anti-proliferative activities of the AIMP2 by competing with AIMP2 for the binding with p53. However, the molecular mechanism for the interaction of p53 and AIMP2 remains elusive. Using NMR spectroscopy, we studied the structural details of the interaction of transactivation domain 1 (TAD1) of p53 with GST domain of AIMP2, which is also common in AIMP2-DX2. The chemical shift perturbation (CSP) experiments demonstrate that amino acid residues from E17 to E28 of p53, known to bind to MDM2 are also involved in binding to AIMP2-DX2. Structure determination of this region based on the transferred-NOE (trNOE) data revealed that TAD1 of the p53 forms a turn structure with hydrophobic interactions by side chains of F19, L22, W23 and L26, distinct from the structure for MDM2 binding. Also, docking results based on NMR CSP data suggest the binding mode of p53 with AIMP2-DX2 GST domain. These data provide the first structural insight into the binding of the p53 TAD1 on AIMP2 and AIMP2-DX2.