http://www.cnr.it/ontology/cnr/individuo/prodotto/ID228958

Structure-Based Design of a Potent Artificial Transactivation Domain Based on p53 (Articolo in rivista)

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Structure-Based Design of a Potent Artificial Transactivation Domain Based on p53 (Articolo in rivista) (literal)

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Langlois, C ; Del Gatto, A ; Arseneault, G ; Lafrance-Vanasse, J ; De Simone, M ; Morse, T 3 ; de Paola, I ; Lussier-Price, M ; Legault, P ; Pedone, C ; Zaccaro, L ; Omichinski, JG (2012)
Structure-Based Design of a Potent Artificial Transactivation Domain Based on p53
in Journal of the American Chemical Society (Print)
(literal)

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Langlois, C ; Del Gatto, A ; Arseneault, G ; Lafrance-Vanasse, J ; De Simone, M ; Morse, T 3 ; de Paola, I ; Lussier-Price, M ; Legault, P ; Pedone, C ; Zaccaro, L ; Omichinski, JG (literal)

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Univ Naples Federico II, CNR, Inst Biostruct & Bioimaging, I-80134 Naples, Italy Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada (literal)

Titolo

Structure-Based Design of a Potent Artificial Transactivation Domain Based on p53 (literal)

Abstract

Malfunctions in transcriptional regulation are associated with a number of critical human diseases. As a result, there is considerable interest in designing artificial transcription activators (ATAs) that specifically control genes linked to human diseases. Like native transcriptional activator proteins, an ATA must minimally contain a DNA-binding domain (DBD) and a transactivation domain (TAD) and, although there are several reliable methods for designing artificial DBDs, designing artificial TADs has proven difficult. In this manuscript, we present a structure-based strategy for designing short peptides containing natural amino acids that function as artificial TADs. Using a segment of the TAD of p53 as the scaffolding, modifications are introduced to increase the helical propensity of the peptides. The most active artificial TAD, termed E-Cap-(LL), is a 13-mer peptide that contains four key residues from p53, an N-capping motif and a dileucine hydrophobic bridge. In vitro analysis demonstrates that E-Cap-(LL) interacts with several known p53 target proteins, while in vivo studies in a yeast model system show that it is a 20-fold more potent transcriptional activator than the native p53-13 peptide. These results demonstrate that structure-based design represents a promising approach for developing artificial TADs that can be combined with artificial DBDs to create potent and specific ATAs. (literal)

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