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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

HNF4α contains the two conserved domains of the nuclear receptor (NR) superfamily - the DNA binding (DBD) and the ligand binding domains (LBD). The DBD consists of two zinc fingers comprised of 4 cysteines each, followed by a hinge region. Like other NRs, the HNF4 LBD is comprised of 12 alpha helices that create a hydrophobic pocket. In bacterially expressed HNF4 a mixture of fatty acids that bound very tightly was found in the ligand binding pocket (LBP) [1][2][3]. In contrast, in mammalian expressed HNF4α only a single fatty acid was found bound, the essential fatty acid linoleic acid (LA) (C18:2). While the binding of LA in the HNF4α pocket is reversible, it has not yet been shown to affect the transactivation function of HNF4α [4].

The region N-terminal to the DBD contains an activation function (AF-1) [5]. In the isoforms driven by the P1 promoter (HNF4α1/2), the AF-1 can activate transcription on its own. The N-terminal region of the P2-driven isoforms (HNF4α7/8) is smaller and appears to lack an AF-1 function [6].

HNF4α also contains an unusually long F domain of ~90 amino acids in the very C-terminal region of the protein. The F domain contains a repressor function that is somewhat alleviated by the insertion of 10 amino acids in the HNF4α2 isoform [7][8].

Ligand Binding Domain structures:

  • [1] - Wisely et al., Structure 2002
  • [2] - Dhe-Paganon et al. JBC 2002
  • [3] - Rha et al. JBC 2009


DNA Binding Domain structure:

  • [4] - Lu et al. JBC 2008
References
  1. Duda K et al. Structural basis for HNF-4alpha activation by ligand and coactivator binding. J. Biol. Chem., 279(22):23311-6. (PMID 14982928)
  2. Dhe-Paganon S et al. Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand. J. Biol. Chem., 277(41):37973-6. (PMID 12193589)
  3. Wisely GB et al. Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. Structure, 10(9):1225-34. (PMID 12220494)
  4. Yuan X et al. Identification of an endogenous ligand bound to a native orphan nuclear receptor. PLoS ONE, 4(5):e5609. (PMID 19440305)
  1. Green VJ et al. Critical structural elements and multitarget protein interactions of the transcriptional activator AF-1 of hepatocyte nuclear factor 4. J. Biol. Chem., 273(45):29950-7. (PMID 9792714)
  2. Torres-Padilla ME et al. Developmentally regulated N-terminal variants of the nuclear receptor hepatocyte nuclear factor 4alpha mediate multiple interactions through coactivator and corepressor-histone deacetylase complexes. J. Biol. Chem., 277(47):44677-87. (PMID 12205093)
  3. Sladek FM et al. Modulation of transcriptional activation and coactivator interaction by a splicing variation in the F domain of nuclear receptor hepatocyte nuclear factor 4alpha1. Mol. Cell. Biol., 19(10):6509-22. (PMID 10490591)
  4. Hadzopoulou-Cladaras M et al. Functional domains of the nuclear receptor hepatocyte nuclear factor 4. J. Biol. Chem., 272(1):539-50. (PMID 8995295)
Structures
About this section
This section contains 3D PDB models of structural predictions for this transcription factor. METHODS: The template selection protocol follows that of Morozov and Siggia, in which templates are selected to optimize similarity of DNA-binding residues (Morozov AV, Siggia ED. PNAS 104(17):7068-73). This has been shown to increase modeling accuracy at the DNA-binding interface. For all solved structures containing DNA, amino acids within 4A of DNA (DNA-binding residues) are stored. Pfam domain hits of each DNA-bound chain are detected by hmmer, and each hit is added to a list mapping domain family name to chain hits. Pfam domain hits of each unsolved structure are detected by HMMER. For each identified Pfam family, the unsolved sequence is aligned to all solved family members (putative templates). Alignments are scored based on similarity of the DNA-binding residues in the template to the aligned residues of the unsolved sequence. For each subsequence of the unsolved protein identified as a DNA-binding domain, the top scoring template is selected. For sequences known to form homodimers, a homodimeric template is selected. The model is constructed from the template using Modeller 9v2. DNA bound to the template is added to the model by superimposition of the solved and modeled structures.
HNF4A 3172 1r0o
Image 3D Model .PDB File
HNF4A 3172 3cbbA
Image 3D Model .PDB File
Family
Zinc-coordinating Group » Hormone-nuclear Receptor Family
AR
Homo sapiens
Ar
Mus musculus
 ESR1
Homo sapiens
 Esr1
Mus musculus
 ESR2
Homo sapiens
 Esr2
Mus musculus
Esrra
Mus musculus
ESRRA
Homo sapiens
Esrrb
Mus musculus
ESRRB
Homo sapiens
Esrrg
Mus musculus
ESRRG
Homo sapiens
 HNF4A
Homo sapiens
 Hnf4a
Mus musculus
Hnf4g
Mus musculus
 HNF4G
Homo sapiens
Nr0b2
Mus musculus
NR0B2
Homo sapiens
Nr1d1
Mus musculus
NR1D1
Homo sapiens
Nr1d2
Mus musculus
NR1D2
Homo sapiens
Nr1h2
Mus musculus
NR1H2
Homo sapiens
Nr1h3
Mus musculus
NR1H3
Homo sapiens
Nr1h4
Mus musculus
NR1H4
Homo sapiens
Nr1h5
Mus musculus
Nr1i2
Mus musculus
NR1I2
Homo sapiens
 Nr1i3
Mus musculus
 NR1I3
Homo sapiens
Nr2c1
Mus musculus
NR2C1
Homo sapiens
Nr2c2
Mus musculus
NR2C2
Homo sapiens
 NR2E1
Homo sapiens
 Nr2e1
Mus musculus
Nr2e3
Mus musculus
NR2E3
Homo sapiens
 Nr2f1
Mus musculus
 NR2F1
Homo sapiens
 Nr2f2
Mus musculus
 NR2F2
Homo sapiens
Nr2f6
Mus musculus
NR2F6
Homo sapiens
 Nr3c1
Mus musculus
 NR3C1
Homo sapiens
Nr3c2
Mus musculus
NR3C2
Homo sapiens
Nr4a1
Mus musculus
NR4A1
Homo sapiens
Nr4a2
Mus musculus
NR4A2
Homo sapiens
Nr4a3
Mus musculus
NR4A3
Homo sapiens
Nr5a1
Mus musculus
NR5A1
Homo sapiens
Nr5a2
Mus musculus
NR5A2
Homo sapiens
Nr6a1
Mus musculus
NR6A1
Homo sapiens
Pgr
Mus musculus
PGR
Homo sapiens
 Ppara
Mus musculus
 PPARA
Homo sapiens
Ppard
Mus musculus
PPARD
Homo sapiens
 Pparg
Mus musculus
 PPARG
Homo sapiens
 Rara
Mus musculus
 RARA
Homo sapiens
 Rarb
Mus musculus
 RARB
Homo sapiens
 Rarg
Mus musculus
 RARG
Homo sapiens
Rora
Mus musculus
RORA
Homo sapiens
Rorb
Mus musculus
RORB
Homo sapiens
Rorc
Mus musculus
RORC
Homo sapiens
Rxra
Mus musculus
RXRA
Homo sapiens
Rxrb
Mus musculus
RXRB
Homo sapiens
Rxrg
Mus musculus
RXRG
Homo sapiens
Thra
Mus musculus
THRA
Homo sapiens
 Thrb
Mus musculus
 THRB
Homo sapiens
Vdr
Mus musculus
VDR
Homo sapiens
 
Figures
FIGURE 5 Domain structure of HNF4α
At the top are the classical domains; at the bottom are the functions. Many co-activators (p300, CBP. SRC1. GRIP1), mediator components, general transcription factors (TFIIB, TBP, TAFs, PC4, ADA2) and transcriptional activators (Smad3/4) have been found to interact with the AF-1 region. The zinc finger (Zn++) plus hinge (H) region is sufficient for DNA binding although the LBD provides the major dimerization motifs in helices 9 and 10. The AF-2 (helix 12) is absolutely required for transactivation and interaction with various co-activators. Other transcriptional activators (HNF1, p53, SHP, SREBPs, COUP-TFs, Sp1) and co-regulators (PGC1, p300, CBP, GRIP1, Src1, ACTR), as well as the co-repressor SMRT, also interact with the LBD. The F domain represses transcription but on its own does not interact with the co-repressor SMRT. See Interaction tab for a more complete list of interacting proteins and references.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.