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| | ==Multi-Domain Organization of the HNF4alpha Nuclear Receptor Complex on DNA== | | ==Multi-Domain Organization of the HNF4alpha Nuclear Receptor Complex on DNA== |
| - | <StructureSection load='4iqr' size='340' side='right' caption='[[4iqr]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='4iqr' size='340' side='right'caption='[[4iqr]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4iqr]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IQR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IQR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4iqr]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IQR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IQR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HNF4A, HNF4, NR2A1, TCF14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4iqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iqr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4iqr RCSB], [http://www.ebi.ac.uk/pdbsum/4iqr PDBsum]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4iqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iqr OCA], [https://pdbe.org/4iqr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4iqr RCSB], [https://www.ebi.ac.uk/pdbsum/4iqr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4iqr ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. [[http://www.uniprot.org/uniprot/HNF4A_HUMAN HNF4A_HUMAN]] Defects in HNF4A are the cause of maturity-onset diabetes of the young type 1 (MODY1) [MIM:[http://omim.org/entry/125850 125850]]; also symbolized MODY-1. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:9313765</ref> <ref>PMID:9243109</ref> <ref>PMID:9449683</ref> | + | [https://www.uniprot.org/uniprot/HNF4A_HUMAN HNF4A_HUMAN] Defects in HNF4A are the cause of maturity-onset diabetes of the young type 1 (MODY1) [MIM:[https://omim.org/entry/125850 125850]; also symbolized MODY-1. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:9313765</ref> <ref>PMID:9243109</ref> <ref>PMID:9449683</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref> [[http://www.uniprot.org/uniprot/HNF4A_HUMAN HNF4A_HUMAN]] Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine. | + | [https://www.uniprot.org/uniprot/HNF4A_HUMAN HNF4A_HUMAN] Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4iqr" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Chandra, V]] | + | [[Category: Large Structures]] |
| - | [[Category: Huang, P]] | + | [[Category: Chandra V]] |
| - | [[Category: Kim, Y]] | + | [[Category: Huang P]] |
| - | [[Category: Rastinejad, F]] | + | [[Category: Kim Y]] |
| - | [[Category: Transcription factor]]
| + | [[Category: Rastinejad F]] |
| - | [[Category: Transcription-dna complex]]
| + | |
| Structural highlights
Disease
HNF4A_HUMAN Defects in HNF4A are the cause of maturity-onset diabetes of the young type 1 (MODY1) [MIM:125850; also symbolized MODY-1. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.[1] [2] [3]
Function
HNF4A_HUMAN Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine.
Publication Abstract from PubMed
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.
Multidomain integration in the structure of the HNF-4alpha nuclear receptor complex.,Chandra V, Huang P, Potluri N, Wu D, Kim Y, Rastinejad F Nature. 2013 Mar 21;495(7441):394-8. doi: 10.1038/nature11966. Epub 2013 Mar 13. PMID:23485969[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, Omori Y, Iwamoto Y, Bell GI. Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes. 1997 Oct;46(10):1652-7. PMID:9313765
- ↑ Bulman MP, Dronsfield MJ, Frayling T, Appleton M, Bain SC, Ellard S, Hattersley AT. A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young. Diabetologia. 1997 Jul;40(7):859-62. PMID:9243109
- ↑ Hani EH, Suaud L, Boutin P, Chevre JC, Durand E, Philippi A, Demenais F, Vionnet N, Furuta H, Velho G, Bell GI, Laine B, Froguel P. A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Invest. 1998 Feb 1;101(3):521-6. PMID:9449683 doi:10.1172/JCI1403
- ↑ Chandra V, Huang P, Potluri N, Wu D, Kim Y, Rastinejad F. Multidomain integration in the structure of the HNF-4alpha nuclear receptor complex. Nature. 2013 Mar 21;495(7441):394-8. doi: 10.1038/nature11966. Epub 2013 Mar 13. PMID:23485969 doi:http://dx.doi.org/10.1038/nature11966
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