Interaction of the p53 DNA-Binding Domain with Its N-Terminal Extension Modulates the Stability of the p53 Tetramer

摘要: The tetrameric tumor suppressor p53 plays a pivotal role in the control of cell cycle and provides paradigm for an emerging class oligomeric, multidomain proteins with structured intrinsically disordered regions. Many its biophysical functional properties have been extrapolated from truncated variants, yet exact structural certain segments protein is unclear. We found NMR X-ray crystallography that DNA-binding domain (DBD) human p53, usually defined as residues 94–292, extends beyond these boundaries. Trp91, hinge region between proline-rich N-terminal DBD, folds back onto latter has cation–π interaction Arg174. These additional interactions increase melting temperature DBD by up to 2 °C inhibit aggregation tetramer. They also modulate dissociation absence Trp91/Arg174 packing presumably allows nonnative DBD–DBD both nucleate stabilize interface. data important implications studies general, highlighting fact weak ordered–disordered can complex structure.