ArticleThe Journal of biological chemistry2009
Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- A Novel SXXLF Motif in the FXR N-Terminal Domain Mediates Coregulator and Interdomain Interactions.Chembiochem : a European journal of chemical biology · 2026Article
- Stomach at the crossroads: nuclear receptor signaling at the interface between what we are and what we eat.Physiological reviews · 2026Review
- Molecular regulation of PGC-1α: from protein-protein interactions and post-translational modifications to pharmacological modulation.Journal of molecular medicine (Berlin, Germany) · 2026Review
- A novel SXXLF motif in the FXR N-terminal domain mediates coregulator and interdomain interactions.bioRxiv : the preprint server for biology · 2026Article
- Mutational landscapes of HNF MODY gene products display a wide distribution with functional implications.Endocrine connections · 2025Review
- Structural basis for the asymmetric binding of coactivator SRC1 to FXR-RXRα and allosteric communication within the complex.Communications biology · 2025Article
- Structure-based identification of HNF4α agonists: Rosmarinic acid as a promising candidate for NAFLD treatment.Computational and structural biotechnology journal · 2025Article
- PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.Cancers · 2022Article
- Article
- Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men.International journal of endocrinology · 2021Review
- Predicting a Kind of Unusual Multiple-States Dimerization-Modes Transformation in Protein PD-L1 System by Computational Investigation and a Generalized Rate Theory.Frontiers in chemistry · 2021Article
- ErbB3-binding protein 1 (EBP1) represses HNF4α-mediated transcription and insulin secretion in pancreatic β-cells.The Journal of biological chemistry · 2019Article
- Differential effects, on oncogenic pathway signalling, by derivatives of the HNF4 α inhibitor BI6015.British journal of cancer · 2019Article
- Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1.Structure (London, England : 1993) · 2019Article
- Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA.Structure (London, England : 1993) · 2017Article
- A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH).Hepatology (Baltimore, Md.) · 2017Article
- Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha.Genome research · 2017Article
- Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α.The Journal of biological chemistry · 2015Article
- Hepatocyte nuclear factor (HNF) 4α transactivation of cytochrome P450 (Cyp) 2d40 promoter is enhanced during pregnancy in mice.Biochemical pharmacology · 2015Article
- Structural insights into gene repression by the orphan nuclear receptor SHP.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
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4 authors.
Funding
Abstract
Hepatocyte nuclear factor 4alpha (HNF4alpha) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4alpha interacts, peroxisome proliferation-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1alpha recruitment, we have determined the crystal structure of HNF4alpha in complex with a fragment of PGC-1alpha containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4alpha toward the LXXLL motifs of PGC-1alpha could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.
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