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Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain.

ABSTRACT: Hsp90 (heat shock protein of 90 kDa) is often found associated with functional domains of client proteins, including those for ligand binding, dimerization, DNA binding, and enzymatic activity. Although Hsp90 can maintain the conformation of functionally important domains prior to activation of the client protein, its specific binding site and the mechanism(s) of Hsp90 dissociation during activation are unknown. Here, we have identified and characterized residues involved in Hsp90 binding within the aryl hydrocarbon receptor (AhR) ligand-binding domain and demonstrate that they overlap with those involved in ligand binding. In agreement with this spatial model, ligand binding results in Hsp90 dissociation from the AhR Per-ARNT-Sim B fragment. Interestingly, whereas Hsp90-binding residues within the ligand-binding domain were not involved in Hsp90-dependent AhR protein stability, several of these residues are important for ligand-dependent AhR activation, and their mutation resulted in conversion of two AhR antagonists/partial agonists into full AhR agonists. These studies reveal co-localization of a tentative Hsp90-binding site with that for AhR ligand binding and provide the first molecular mechanism for Hsp90 dissociation in the activation of a client protein.

SUBMITTER: Soshilov A

PROVIDER: S-EPMC3186366 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain.

Soshilov Anatoly A Denison Michael S MS

The Journal of biological chemistry 20110819 40

Hsp90 (heat shock protein of 90 kDa) is often found associated with functional domains of client proteins, including those for ligand binding, dimerization, DNA binding, and enzymatic activity. Although Hsp90 can maintain the conformation of functionally important domains prior to activation of the client protein, its specific binding site and the mechanism(s) of Hsp90 dissociation during activation are unknown. Here, we have identified and characterized residues involved in Hsp90 binding within ...[more]

PMID: 21856752

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Project description:Greater than 90% of significant genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) are in noncoding regions of the genome, but only 25.6% are known expression quantitative trait loci (eQTLs). Therefore, the function of many significant GWAS SNPs remains unclear. We have identified a novel type of eQTL for which SNPs distant from ligand-activated transcription factor (TF) binding sites can alter target gene expression in a SNP genotype-by-ligand-dependent fashion that we refer to as pharmacogenomic eQTLs (PGx-eQTLs)-loci that may have important pharmacotherapeutic implications. In the present study, we integrated chromatin immunoprecipitation-seq with RNA-seq and SNP genotype data for a panel of lymphoblastoid cell lines to identify 10 novel cis PGx-eQTLs dependent on the ligand-activated TF aryl hydrocarbon receptor (AHR)-a critical environmental sensor for xenobiotic (drug) and immune response. Those 10 cis PGx-eQTLs were eQTLs only after AHR ligand treatment, even though the SNPs did not create/destroy an AHR response element-the DNA sequence motif recognized and bound by AHR. Additional functional studies in multiple cell lines demonstrated that some cis PGx-eQTLs are functional in multiple cell types, whereas others displayed SNP-by-ligand-dependent effects in just one cell type. Furthermore, four of those cis PGx-eQTLs had previously been associated with clinical phenotypes, indicating that those loci might have the potential to inform clinical decisions. Therefore, SNPs across the genome that are distant from TF binding sites for ligand-activated TFs might function as PGx-eQTLs and, as a result, might have important clinical implications for interindividual variation in drug response. SIGNIFICANCE STATEMENT: More than 90% of single-nucleotide polymorphisms (SNPs) that are associated with clinical phenotypes are located in noncoding regions of the genome. However, the mechanisms of action of many of those SNPs have not been elucidated, and drugs may unmask functional expression quantitative trail loci (eQTLs). In the current study, we used drugs that bind to the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and identified SNPs that were associated with interindividual variation in gene expression following drug exposure-termed pharmacogenomic (PGx)-eQTLs. Possibly of greater significance, those PGx-eQTL SNPs were outside of AHR binding sites, indicating that they do not interrupt AHR DNA recognition. PGx-eQTLs such as those described in this work may have crucial implications for interindividual variation in drug.

Dataset Information

Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain.

Publications

Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain.

Similar Datasets

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