HYDROPHOBIC SIDE-CHAIN SIZE IS A DETERMINANT OF THE 3-DIMENSIONAL STRUCTURE OF THE P53 OLIGOMERIZATION DOMAIN

The p53 tumor suppressor oligomerization domain, a dimer of two primar y dimers, is an independently folding domain whose subunits consist of a beta-strand, a tig ht turn anti an alpha-helix. To evaluate the eff ect of hydrophobic side-chains on three-dimensional structure, we subs tituted residues Phe341 and Leu344 in the a-helix with other hydrophob ic amino acids. Substitutions that resulted in residue 341 having a sm aller side-chain than residue 344 snitched the stoichiometry of the do main front tetrameric to dimeric, The three-dimensional structure of o ne such dimer was determined by multidimensional NMR spectroscopy, Whe n compared with the primary dimer of the wild-type p53 oligomerization domain, the mutant dimer showed a snitch in alpha-helical packing fro m anti-parallel to parallel and rotation of the alpha-helices relative to the beta-strands, Hydrophobic side-chain size is therefore an impo rtant determinant of a protein fold.