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The p73 DNA binding domain displays enhanced stability relative to its homologue, the tumor suppressor p53, and exhibits cooperative DNA binding.
Patel, Seema; Bui, Tam T T; Drake, Alex F; Fraternali, Franca; Nikolova, Penka V.
Afiliação
  • Patel S; Department of Biochemistry, School of Biomedical & Health Sciences, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
Biochemistry ; 47(10): 3235-44, 2008 Mar 11.
Article em En | MEDLINE | ID: mdl-18260640
ABSTRACT
The p53 protein family is involved in the control of an intricate network of genes implicated in cell cycle, through to germ line integrity and development. Although the role of p53 is well-established, the intrinsic nature of its homologue p73 has yet to be fully elucidated. Here, the biochemical characterization and homology-based modeling of the p73 protein is presented and the implications for its function(s) examined. The DNA binding domains (DBDs) of p53, p63, and p73 bind to the specific target site of a 30-mer gadd45 dsDNA, as tested by EMSA. The monomeric DBDs bind cooperatively forming tetrameric complexes. However, a larger construct consisting of p73 DBD plus TET domain (p73 CT) and the corresponding p53 DBD plus TET domain (p53 CT) bind gadd45 differently than the respective DBDs. Significantly, p73 DBD exhibited enhanced thermodynamic stability relative to the p53 DBD but not compared to p63 DBD as shown by DSC, CD, and equilibrium unfolding. The p73 CT is less stable than p73 DBD. The modeling data show distinct electrostatic surfaces of p73 and p53 dimers when bound to DNA. Specifically, the p73 surface is less complementary for DNA binding, which may account for the differences in affinity and specificity for p53 REs. These stability and DNA binding data for p73 in vitro enhance and complement our understanding of the role of the p73 protein in vivo and could be exploited in designing strategies for cancer therapy in places where p53 is mutated.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Proteína Supressora de Tumor p53 / Proteínas Supressoras de Tumor / Proteínas de Ligação a DNA Limite: Humans Idioma: En Ano de publicação: 2008 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Proteína Supressora de Tumor p53 / Proteínas Supressoras de Tumor / Proteínas de Ligação a DNA Limite: Humans Idioma: En Ano de publicação: 2008 Tipo de documento: Article