6cht

From Proteopedia

HNF4alpha in complex with the corepressor EBP1 fragment

PDB ID 6cht

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Structural highlights

6cht is a 20 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.174Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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