title: Structure and stability insights into tumour suppressor p53 evolutionary related proteins.
abstract: The p53 family of genes and their protein products, namely, p53, p63 and p73, have over one billion years of evolutionary history. Advances in computational biology and genomics are enabling studies of the complexities of the molecular evolution of p53 protein family to decipher the underpinnings of key biological conditions spanning from cancer through to various metabolic and developmental disorders and facilitate the design of personalised medicines. However, a complete understanding of the inherent nature of the thermodynamic and structural stability of the p53 protein family is still lacking. This is due, to a degree, to the lack of comprehensive structural information for a large number of homologous proteins and to an incomplete knowledge of the intrinsic factors responsible for their stability and how these might influence function. Here we investigate the thermal stability, secondary structure and folding properties of the DNA-binding domains (DBDs) of a range of proteins from the p53 family using biophysical methods. While the N- and the C-terminal domains of the p53 family show sequence diversity and are normally targets for post-translational modifications and alternative splicing, the central DBD is highly conserved. Together with data obtained from Molecular Dynamics simulations in solution and with structure based homology modelling, our results provide further insights into the molecular properties of evolutionary related p53 proteins. We identify some marked structural differences within the p53 family, which could account for the divergence in biological functions as well as the subtleties manifested in the oligomerization properties of this family.
authors.affiliation: King's College London, School of Biomedical Sciences, Department of Biochemistry & Randall Division of Cell and Molecular Biophysics, New Hunt's House, London, United Kingdom ; Department of Pharmacy, University of Naples "Federico II", Napoli, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pagano
authors.forename: Abdullah
authors.initials: A
authors.lastname: Jama
authors.forename: Pierre
authors.initials: P
authors.lastname: Martinez
authors.forename: Ester
authors.initials: E
authors.lastname: Akanho
authors.forename: Tam T T
authors.initials: TT
authors.lastname: Bui
authors.forename: Alex F
authors.initials: AF
authors.lastname: Drake
authors.forename: Franca
authors.initials: F
authors.lastname: Fraternali
authors.forename: Penka V
authors.initials: PV
authors.lastname: Nikolova
mesh_terms: D000595:Amino Acid Sequence; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53