Structure-based design of a potent artificial transactivation domain based on p53(425 views) Langlois C, Del Gatto A, Arseneault G, Lafrance-vanasse J, De Simone M, Morse T, De Paola I, Lussier-price M, Legault P, Pedone C, Zaccaro L, Omichinski JG
J Am Chem Soc (ISSN: 1520-5126, 0002-2786, 0002-7863), 2012 Jan 25; 134(3): 1715-1723.
Keywords: Dna-Binding Domain, Human Disease, In-Vitro Analysis, Model System, N-Capping Motif, Natural Amino Acids, Structure-Based, Target Proteins, Transactivation Domain, Transcription Activators, Transcriptional Activators, Transcriptional Regulation, Disease Control, Genes, Peptides, Structural Design, Protein P53, Article, Capping Phenomenon, Controlled Study, Nonhuman, Protein Modification, Protein Motif, Protein Structure, Yeast, Amino Acid Motifs, Amino Acid Sequence, Gene Expression Regulation, Fungal, Leucine, Molecular, Molecular Sequence Data, Tertiary, Transcriptional Activation, Tumor Suppressor Protein P53, Chemistry, Chemical Synthesis, Metabolism, Genetics,
Affiliations: *** IBB - CNR ***
D partement de Biochimie, Universit de Montr al, C. P. 6128 Succursale, Centre-Ville, Montr al, QC H3C 3J7, Canada
Institute of Biostructures and Bioimaging, Department of Biological Sciences, University of Naples Federico II, via Mezzocannone 16, 80134 Napoli, Italy
Departement de Biochimie, Universite de Montreal, C. P. 6128 Succursale, Centre-Ville, Montreal, Quebec H3C 3J7, Canada.
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Structure-based design of a potent artificial transactivation domain based on p53
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. 2011 American Chemical Society
Structure-based design of a potent artificial transactivation domain based on p53