Mechanism of folding and assembly of a small tetrameric protein domain from tumor suppressor p53.
We have analyzed the folding pathway of the tetramerization domain of the tumor suppressor protein p53. Structures of transition states were determined from phi-values for 25 mutations, including leucine to norvaline, and the analysis encompassed nearly every residue in the domain. Denatured monomers fold and dimerize, through a transition state with little native structure, to form a transient, highly structured dimeric intermediate. The intermediate dimerizes, through a native-like transition state with the primary dimers fully folded but with interdimer interactions only partially formed, to form the native tetramer as a 'dimer of dimers'.
Cambridge University Chemical Laboratory and Cambridge Centre for Protein Engineering, MRC Centre, UK.
M G
MG
Mateu
M M
MM
Sánchez Del Pino
A R
AR
Fersht
D001704:Biopolymers; D002942:Circular Dichroism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017510:Protein Folding; D013050:Spectrometry, Fluorescence; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics
D001704:Biopolymers; D016159:Tumor Suppressor Protein p53