6CHT

HNF4alpha in complex with the corepressor EBP1 fragment

Summary for 6CHT

• Entry DOI: 10.2210/pdb6cht/pdb
• Descriptor: Hepatocyte nuclear factor 4-alpha, Proliferation-associated protein 2G4, LAURIC ACID, ... (4 entities in total)
• Functional Keywords: hnf4alpha, ebp1, nuclear receptor, co-repressor, protein-protein interaction, gene regulation, insulin secretion, diabetes, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 20
• Total formula weight: 450999.28

Authors

Chi, Y.I.,Singh, P.,Lee, I.K. (deposition date: 2018-02-22, release date: 2019-02-27, Last modification date: 2024-12-25)

Primary citation

Han, E.H.,Singh, P.,Lee, I.K.,Urrutia, R.,Chi, Y.I.
ErbB3-binding protein 1 (EBP1) represses HNF4 alpha-mediated transcription and insulin secretion in pancreatic beta-cells.
J.Biol.Chem., 294:13983-13994, 2019

PubMed Abstract: HNF4α (hepatocyte nuclear factor 4α) is one of the master regulators of pancreatic β-cell development and function, and mutations in the α gene are well-known monogenic causes of diabetes. As a member of the nuclear receptor family, HNF4α exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge of the different functional complexes in which HNF4α participates. Here, to find HNF4α-binding proteins in pancreatic β-cells, we used yeast two-hybrid screening, a mammalian two-hybrid assay, and glutathione -transferase pulldown approaches, which identified EBP1 (ErbB3-binding protein 1) as a factor that binds HNF4α in a LLL motif-mediated manner. In the β-cells, EBP1 suppressed the expression of HNF4α target genes that are implicated in insulin secretion, which is impaired in HNF4α mutation-driven diabetes. The crystal structure of the HNF4α ligand-binding domain in complex with a peptide harboring the EBP1 LLL motif at 3.15Å resolution hinted at the molecular basis of the repression. The details of the structure suggested that EBP1's LLL motif competes with HNF4α 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 HNF4α-EBP1 interaction or tissue-specific EBP1 inactivation can enhance HNF4α activities and thereby improve insulin secretion in β-cells, potentially representing a new strategy for managing diabetes and related metabolic disorders.

PubMed: 31362984
DOI: 10.1074/jbc.RA119.009558

Experimental method

X-RAY DIFFRACTION (3.174 Å)