title: Hydrophobic side-chain size is a determinant of the three-dimensional structure of the p53 oligomerization domain.
abstract: The p53 tumor suppressor oligomerization domain, a dimer of two primary dimers, is an independently folding domain whose subunits consist of a beta-strand, a tight turn and an alpha-helix. To evaluate the effect of hydrophobic side-chains on three-dimensional structure, we substituted residues Phe341 and Leu344 in the alpha-helix with other hydrophobic amino acids. Substitutions that resulted in residue 341 having a smaller side-chain than residue 344 switched the stoichiometry of the domain from tetrameric to dimeric. The three-dimensional structure of one such dimer was determined by multidimensional NMR spectroscopy. When compared with the primary dimer of the wild-type p53 oligomerization domain, the mutant dimer showed a switch in alpha-helical packing from anti-parallel to parallel and rotation of the alpha-helices relative to the beta-strands. Hydrophobic side-chain size is therefore an important determinant of a protein fold.
authors.affiliation: Departments of Molecular Genetics and Structural Biology, The Wistar Institute, Philadelphia, PA 19104-4268, USA.
authors.forename: M
authors.initials: M
authors.lastname: McCoy
authors.forename: E S
authors.initials: ES
authors.lastname: Stavridi
authors.forename: J L
authors.initials: JL
authors.lastname: Waterman
authors.forename: A M
authors.initials: AM
authors.lastname: Wieczorek
authors.forename: S J
authors.initials: SJ
authors.lastname: Opella
authors.forename: T D
authors.initials: TD
authors.lastname: Halazonetis
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53