4IQR: Multi-domain Organization Of The Hnf4alpha Nuclear Receptor Complex On Dna

Citation:
Abstract
The hepatocyte nuclear factor 4alpha (HNF-4alpha; 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-4alpha is the most abundant DNA-binding protein in the liver, where some 40% of the actively transcribed genes have a HNF-4alpha response element. These regulated genes are largely involved in the hepatic gluconeogenic program and lipid metabolism. In the pancreas HNF-4alpha is also a master regulator, controlling an estimated 11% of islet genes. HNF-4alpha 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 A crystal structure of the multidomain human HNF-4alpha 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-4alpha homodimer is different from that of the PPAR-gamma-RXR-alpha 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.
PDB ID: 4IQRDownload
MMDB ID: 108487
PDB Deposition Date: 2013/1/13
Updated in MMDB: 2013/10
Experimental Method:
x-ray diffraction
Resolution: 2.9  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4IQR: hexameric; determined by author and by software (PISA)
Molecular Components in 4IQR
Label Count Molecule
Proteins (4 molecules)
2
Hepatocyte Nuclear Factor 4-alpha(Gene symbol: HNF4A)
Molecule annotation
2
Nuclear Receptor Coactivator 2(Gene symbol: NCOA2)
Molecule annotation
Nucleotides(2 molecules)
1
DNA (5'- D(*gp*gp*ap*ap*cp*tp*ap*gp*gp*tp*cp*ap*ap*ap*gp*gp*tp*cp*ap*g)-3')
Molecule annotation
1
DNA (5'- D(*cp*cp*tp*gp*ap*cp*cp*tp*tp*tp*gp*ap*cp*cp*tp*ap*gp*tp*tp*c)-3')
Molecule annotation
Chemicals (6 molecules)
1
2
2
4
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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