Measuring the energetic penalty of folding and binding between p53 and MDM2

Abstract

P53 is a tumor suppressor and transcription factor that is stabilized and activated by cellular stress. P53 contains a disordered transactivation domain (TAD) (residues 1-40) that becomes helical at residues 19-25 when bound to its inhibitors, MDM2 and MDMX. Previous studies from our lab have shown that increasing the transient helicity of p53TAD using mutagenesis increased the affinity with MDM2. We hypothesized this was due to a reduction in the entropic penalty of coupled folding and binding.