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Structural effects of the L145Q, V157F, and R282W cancer-associated mutations in the p53 DNA-binding core domain.
Calhoun, Sara; Daggett, Valerie.
Afiliação
  • Calhoun S; Department of Bioengineering, University of Washington, Seattle, WA 98195-5013, USA.
Biochemistry ; 50(23): 5345-53, 2011 Jun 14.
Article em En | MEDLINE | ID: mdl-21561095
The p53 tumor suppressor is a transcription factor involved in many important signaling pathways, such as apoptosis and cell-cycle arrest. In over half of human cancers, p53 function is compromised by a mutation in its gene. Mutations in the p53 DNA-binding core domain destabilize the structure and reduce DNA-binding activity. We performed molecular dynamics simulations at physiological temperature to study the structural and dynamic effects of the L145Q, V157F, and R282W cancer-associated mutations in comparison to the wild-type protein. While there were common regions of destabilization in the mutant simulations, structural changes particular to individual mutations were also observed. Significant backbone deviations of the H2 helix and S7-S8 loop were observed in all mutant simulations; the H2 helix binds to DNA. In addition, the L145Q and V157F mutations, which are located in the ß-sandwich core of the domain, disrupted the ß-sheet structure and the loop-sheet-helix motif. The R282W mutation caused distortion of the loop-sheet-helix motif, but otherwise this mutant was similar to the wild-type structure. The introduction of these mutations caused rearrangement of the DNA-binding surface, consistent with their reduced DNA-binding activity. The simulations reveal detailed effects of the mutations on the stability and dynamics of p53 that may provide insight for therapeutic approaches.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Proteína Supressora de Tumor p53 / Mutação / Neoplasias Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Biochemistry Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Proteína Supressora de Tumor p53 / Mutação / Neoplasias Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Biochemistry Ano de publicação: 2011 Tipo de documento: Article