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Multidomain integration in the structure of the HNF-4α nuclear receptor complex
Open accessAbstract
The hepatocyte nuclear factor 4α (HNF-4α; also known as NR2A1) is a member of the nuclear receptor (NR) family of transcription factors, which have conserved DNA-binding domains and ligand-binding domains. HNF-4α is the most abundant DNA-binding protein in the liver, where some 40% of the actively transcribed genes have a HNF-4α response element. These regulated genes are largely involved in the hepatic gluconeogenic program and lipid metabolism. In the pancreas HNF-4α is also a master regulator, controlling an estimated 11% of islet genes. HNF-4α protein mutations are linked to maturity-onset diabetes of the young, type 1 (MODY1) and hyperinsulinaemic hypoglycaemia. Previous structural analyses of NRs, although productive in elucidating the structure of individual domains, have lagged behind in revealing the connectivity patterns of NR domains. Here we describe the 2.9 Å crystal structure of the multidomain human HNF-4α homodimer bound to its DNA response element and coactivator-derived peptides. A convergence zone connects multiple receptor domains in an asymmetric fashion, joining distinct elements from each monomer. An arginine target of PRMT1 methylation protrudes directly into this convergence zone and sustains its integrity. A serine target of protein kinase C is also responsible for maintaining domain-domain interactions. These post-translational modifications lead to changes in DNA binding by communicating through the tightly connected surfaces of the quaternary fold. We find that some MODY1 mutations, positioned on the ligand-binding domain and hinge regions of the receptor, compromise DNA binding at a distance by communicating through the interjunctional surfaces of the complex. The overall domain representation of the HNF-4α homodimer is different from that of the PPAR-γ-RXR-α heterodimer, even when both NR complexes are assembled on the same DNA element. Our findings suggest that unique quaternary folds and interdomain connections in NRs could be exploited by small-molecule allosteric modulators that affect distal functions in these polypeptides.
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“This LBD-DBD domain arrangement is similar to the HNF4α dimer that was solved by X-ray crystallography (Chandra et al., 2013), which is different from the non-symmetric PPARγ-RXRα dimer (Chandra et al., 2008) or the X-shape LBD-DBD crossing arrangement in RXRα-LXRβ dimer (Lou et al., 2014).”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Chandra et al., 2013
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“Previously published full-length nuclear hormone receptor structures (Chandra et al., 2008; Chandra et al., 2013; Lou et al., 2014; Orlov et al., 2012) also do not present any NTD information.”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Chandra et al., 2013
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Hepatic PRMT1 ameliorates diet-induced hepatic steatosis via induction of PGC1α
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RXR Agonist Modulates TR: Corepressor Dissociation Upon 9-cis Retinoic Acid Treatment
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The Nuclear Receptor Superfamily at Thirty
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Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics
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“In line with the nuclear receptor’s mode of action [3], we observed dimerization of the HNF4α LBD protein and dimer dissociation upon dilution, which hindered inverse ITC experiments.”
BackgroundMethodInfluentialGenomic Analysis of Oral Lichen Planus and Related Oral Microbiome Pathogens
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Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication
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Targeting Nuclear Receptors with Marine Natural Products
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Establishment of a 3D hyperuricemia model based on cultured human liver organoids
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Structural insights into the HNF4 biology
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“The crystal structure shows the topological arrangement of the two homodimer domains (DBD and LBD) on the DR1cons DNA, with the LBD dimer sitting on the DBD dimer and making extensive interactions through helix H9 and the loop 9-10 of the 3’-LBD with the 5’-DBD. Note however that the hinge regions of the two subunits…”
BackgroundMethodInfluentialAllosteric mechanisms of nuclear receptors: insights from computational simulations
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“Communication through the intra-domain junction of the quaternary fold found in NRs such as HNF4-a showed that these signals travel large distances to modulate this DNA binding (Chandra et al., 2013).”
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The protein architecture and allosteric landscape of HNF4α
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“The activities of NRs can be subject to regulation by a variety of different post-translational modi fi cations (PTMs).”
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Dimerization of Nuclear Receptors
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Modulation of nuclear receptor function: Targeting the protein-DNA interface
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Hidden modes of DNA binding by human nuclear receptors
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CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver
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“It is widely accepted that the sequence of the 59-flanking region (6- or 7-bp segment) in addition to the consensus DR1 sequence is important for binding of PPAR to various PPREs (Palmer et al., 1995; Juge-Aubry et al., 1997; Chandra et al., 2013).”
BackgroundSteroid receptor-coregulator transcriptional complexes: new insights from CryoEM
Yi, P., Yu, X., Wang, Z., & O’Malley, B. W. (2021) · Essays in Biochemistry · doi:10.1042/ebc20210019 · Cited by 24
“NRs and most coactivators contain intrinsic disordered regions.”
BackgroundInfluentialStructural basis of the farnesoid X receptor/retinoid X receptor heterodimer on inverted repeat DNA
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Allosteric communications between domains of nuclear receptors
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Computational Detection of Stage-Specific Transcription Factor Clusters during Heart Development
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“Furthermore, the role of HNF4-genes, which where frequently reported to be associated with lipid metabolism in the liver (Watt et al., 2003; Chandra et al., 2013), during cardiac development is still unclear, but may point to changes in the metabolism at this stage.”
BackgroundPeptidylprolyl Isomerase Pin1 Directly Enhances the DNA Binding Functions of Estrogen Receptor α
Rajbhandari, P., Ozers, M. S., Solodin, N. M., Warren, C. L., & Alarid, E. T. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.621698 · Cited by 21
“However, recent crystal and solution structural studies of full-length NRs highlight the signaling convergence of several NR domains via interactive protein surfaces (17, 18).”
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“S2), we superposed the crystal structure of the NR2E3 LBD dimer [Tan et al., 2013] onto the crystal structure of the NR2A1 homodimer bound to DNA [Chandra et al., 2013] to situate NR2E3 LBD missense variants in the context of an overall homodimer structure (Fig.”
BackgroundMethodInfluentialMartínez‐Calle, M., Courbon, G., Hunt-Tobey, B., Francis, C., Spindler, J. J., Wang, X., dos Reis, L. M., Martins, C. S. W., Salusky, I. B., Malluche, H. H., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci159928 · Cited by 17
“Finally, HNF4α activity in osteoblasts also largely regulates known HNF4α-responsive genes involved in glycolytic and lipid metabolism as well as cell response to xenobiotics, similar to observed functions of HNF4α in other organs (63, 64), suggesting a “conserved” function for HNF4α, irrespective of the organ.”
Background
Metadata
- Authors
- Chandra, V., Huang, P., Potluri, N., Wu, D., Kim, Y., & Rastinejad, F.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Argonne National Laboratory (US)
- Corresponding author
- Rastinejad, Fraydoon
- Venue
- Nature
- Published
- 2013-03
- Volume
- 495
- Issue
- 7441
- Pages
- 394-398
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3606643
- OpenAlex
- W2025155497
- Cited by
- 206
- References
- 28
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 11 · 2023: 19 · 2022: 18 · 2021: 11 · 2020: 17 · 2019: 14 · 2018: 15 · 2017: 10 · 2016: 17 · 2015: 20 · 2014: 16 · 2013: 10
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Lirias (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097475, R01DK094147)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HNF4α, nuclear receptors, DNA response elements, coactivator peptide, homodimer, protein kinase C phosphorylation, post-translational modification, maturity-onset diabetes of the young, transcriptional regulation
- MeSH terms
- Humans, Hypoglycemia, Models, Molecular, Mutation, Protein Binding, Point Mutation, Protein Structure, Tertiary, Protein Structure, Quaternary, Hepatocyte Nuclear Factor 4
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