Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HTLV-1 transcriptional activator Tax is required for viral replication and pathogenesis. In concert with human CREB, Tax recruits the human transcriptional coactivator and histone acetyltransferase p300/CBP to the HTLV-1 promoter. Here we investigate the structural features of the interaction between Tax and the KIX domain of p300/CBP. Circular dichroism spectroscopy, nuclear magnetic resonance chemical shift perturbation mapping, and sedimentation equilibrium analysis show that KIX binds a Tax subdomain corresponding to residues 59-98 of Tax (called Tax(59-98)). Circular dichroism spectroscopy suggests that Tax(59-98) is intrinsically disordered (natively unfolded) in isolation and adopts an ordered conformation upon binding KIX. The interaction is disrupted by a single amino acid variation of Tax(59-98) in which leucine 68 is substituted with proline. Chemical shift perturbation mapping reveals that the Tax-binding surface of KIX is distinct from that utilized by CREB, and corresponds to the site of KIX that interacts with the human transcription factors c-Jun and mixed lineage leukemia protein (MLL). Sedimentation equilibrium analysis shows that Tax and the phosphorylated KID domain of CREB can simultaneously bind KIX to form a ternary 1:1:1 complex. The results provide a molecular description of the concerted recruitment of p300/CBP via the KIX domain by Tax and phosphorylated CREB during Tax-mediated gene expression.
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PMID:KIX-mediated assembly of the CBP-CREB-HTLV-1 tax coactivator-activator complex. 1458 Jan 93

We recently described a pair of ligands, PPKID4(P) (4(P)) and PPKID6(U) (6(U)), which present the alpha-helical functional epitope found on helix B of the CREB KID activation domain (KID(P)) on a pancreatic fold protein scaffold. 4(P) and 6(U) bind the natural target of KID(P), the KIX domain of the coactivator CBP, with equilibrium dissociation constants between 515 nM and 1.5 microM and compete effectively with KID(P) for binding to CBP KIX (KIX). Here we present a detailed investigation of the binding mode, orientation, and transcriptional activation potential of 4(P) and 6(U). Equilibrium binding experiments using a panel of well-characterized KIX variants support a model in which 4(P) binds KIX in a manner that closely resembles that of KID(P) but 6(U) binds an overlapping, yet distinct region of the protein. Equilibrium binding experiments using a judiciously chosen panel of 4(P) variants containing alanine or sarcosine substitutions along the putative alpha- or PPII helix of 4(P) support a model in which 4(P) folds into a pancreatic fold structure upon binding to KIX. Transcriptional activation assays performed in HEK293 cells using GAL4 DNA-binding domain fusion proteins indicate that 4(P) functions as a potent activator of p300/CBP-dependent transcription. Notably, 6(U) is a less potent transcriptional activator in this context than 4(P)despite the similarity of their affinities for CBP KIX. This final result suggests that thermodynamic affinity is an important, although not exclusive, criterion controlling the level of KIX-dependent transcriptional activation.
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PMID:Binding mode and transcriptional activation potential of high affinity ligands for the CBP KIX domain. 1579 30