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| | ==HNF4alpha in complex with the corepressor EBP1 fragment== | | ==HNF4alpha in complex with the corepressor EBP1 fragment== |
| - | <StructureSection load='6cht' size='340' side='right' caption='[[6cht]], [[Resolution|resolution]] 3.17Å' scene=''> | + | <StructureSection load='6cht' size='340' side='right'caption='[[6cht]], [[Resolution|resolution]] 3.17Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cht]] is a 20 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CHT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CHT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cht]] is a 20 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=6CHT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CHT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DAO:LAURIC+ACID'>DAO</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]] 3.174Å</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=6cht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cht OCA], [http://pdbe.org/6cht PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cht RCSB], [http://www.ebi.ac.uk/pdbsum/6cht PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cht ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DAO:LAURIC+ACID'>DAO</scene></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=6cht FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cht OCA], [https://pdbe.org/6cht PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cht RCSB], [https://www.ebi.ac.uk/pdbsum/6cht PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cht ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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/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. [[http://www.uniprot.org/uniprot/PA2G4_HUMAN PA2G4_HUMAN]] May play a role in a ERBB3-regulated signal transduction pathway. Seems be involved in growth regulation. Acts a corepressor of the androgen receptor (AR) and is regulated by the ERBB3 ligand neuregulin-1/heregulin (HRG). Inhibits transcription of some E2F1-regulated promoters, probably by recruiting histone acetylase (HAT) activity. Binds RNA. Associates with 28S, 18S and 5.8S mature rRNAs, several rRNA precursors and probably U3 small nucleolar RNA. May be involved in regulation of intermediate and late steps of rRNA processing. May be involved in ribosome assembly. Mediates cap-independent translation of specific viral IRESs (internal ribosomal entry site) (By similarity).<ref>PMID:11268000</ref> <ref>PMID:12682367</ref> <ref>PMID:15064750</ref> <ref>PMID:15583694</ref> | + | [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;"> |
| | + | == Publication Abstract from PubMed == |
| | + | HNF4alpha (hepatocyte nuclear factor 4alpha) is one of the master regulators of pancreatic beta-cell development and function, and mutations in the HNF4alpha gene are well-known monogenic causes of diabetes. As a member of the nuclear receptor family, HNF4alpha exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge of the different functional complexes in which HNF4alpha participates. Here, to find HNF4alpha-binding proteins in pancreatic beta-cells, we used yeast two-hybrid screening, a mammalian two-hybrid assay, and glutathione S-transferase pulldown approaches, which identified EBP1 (ErbB3-binding protein 1) as a factor that binds HNF4alpha in a LXXLL motif-mediated manner. In the beta-cells, EBP1 suppressed the expression of HNF4alpha target genes that are implicated in insulin secretion, which is impaired in HNF4alpha mutation-driven diabetes. The crystal structure of the HNF4alpha ligand-binding domain in complex with a peptide harboring the EBP1 LXXLL motif at 3.15A resolution hinted at the molecular basis of the repression. The details of the structure suggested that EBP1's LXXLL motif competes with HNF4alpha coactivators for the same binding pocket and thereby prevents recruitment of additional transcriptional coactivators. These findings provide further evidence that EBP1 plays multiple cellular roles and is involved in nuclear receptor-mediated gene regulation. Selective disruption of the HNF4alpha-EBP1 interaction or tissue-specific EBP1 inactivation can enhance HNF4alpha activities and thereby improve insulin secretion in beta-cells, potentially representing a new strategy for managing diabetes and related metabolic disorders. |
| | + | |
| | + | ErbB3-binding protein 1 (EBP1) represses HNF4alpha-mediated transcription and insulin secretion in pancreatic beta-cells.,Han EH, Singh P, Lee IK, Urrutia R, Chi YI J Biol Chem. 2019 Sep 20;294(38):13983-13994. doi: 10.1074/jbc.RA119.009558. Epub, 2019 Jul 30. PMID:31362984<ref>PMID:31362984</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6cht" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chi, Y I]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Lee, I K]] | + | [[Category: Large Structures]] |
| - | [[Category: Singh, P]] | + | [[Category: Chi YI]] |
| - | [[Category: Co-repressor]] | + | [[Category: Lee IK]] |
| - | [[Category: Diabetes]] | + | [[Category: Singh P]] |
| - | [[Category: Ebp1]]
| + | |
| - | [[Category: Gene regulation]]
| + | |
| - | [[Category: Hnf4alpha]]
| + | |
| - | [[Category: Insulin secretion]]
| + | |
| - | [[Category: Nuclear receptor]]
| + | |
| - | [[Category: Protein-protein interaction]]
| + | |
| - | [[Category: Transcription]]
| + | |
| 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
HNF4alpha (hepatocyte nuclear factor 4alpha) is one of the master regulators of pancreatic beta-cell development and function, and mutations in the HNF4alpha gene are well-known monogenic causes of diabetes. As a member of the nuclear receptor family, HNF4alpha exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge of the different functional complexes in which HNF4alpha participates. Here, to find HNF4alpha-binding proteins in pancreatic beta-cells, we used yeast two-hybrid screening, a mammalian two-hybrid assay, and glutathione S-transferase pulldown approaches, which identified EBP1 (ErbB3-binding protein 1) as a factor that binds HNF4alpha in a LXXLL motif-mediated manner. In the beta-cells, EBP1 suppressed the expression of HNF4alpha target genes that are implicated in insulin secretion, which is impaired in HNF4alpha mutation-driven diabetes. The crystal structure of the HNF4alpha ligand-binding domain in complex with a peptide harboring the EBP1 LXXLL motif at 3.15A resolution hinted at the molecular basis of the repression. The details of the structure suggested that EBP1's LXXLL motif competes with HNF4alpha coactivators for the same binding pocket and thereby prevents recruitment of additional transcriptional coactivators. These findings provide further evidence that EBP1 plays multiple cellular roles and is involved in nuclear receptor-mediated gene regulation. Selective disruption of the HNF4alpha-EBP1 interaction or tissue-specific EBP1 inactivation can enhance HNF4alpha activities and thereby improve insulin secretion in beta-cells, potentially representing a new strategy for managing diabetes and related metabolic disorders.
ErbB3-binding protein 1 (EBP1) represses HNF4alpha-mediated transcription and insulin secretion in pancreatic beta-cells.,Han EH, Singh P, Lee IK, Urrutia R, Chi YI J Biol Chem. 2019 Sep 20;294(38):13983-13994. doi: 10.1074/jbc.RA119.009558. Epub, 2019 Jul 30. PMID:31362984[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
- ↑ Han EH, Singh P, Lee IK, Urrutia R, Chi YI. ErbB3-binding protein 1 (EBP1) represses HNF4alpha-mediated transcription and insulin secretion in pancreatic beta-cells. J Biol Chem. 2019 Sep 20;294(38):13983-13994. doi: 10.1074/jbc.RA119.009558. Epub, 2019 Jul 30. PMID:31362984 doi:http://dx.doi.org/10.1074/jbc.RA119.009558
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