title: The activation function 2 domain of hepatic nuclear factor 4 is regulated by a short C-terminal proline-rich repressor domain.
abstract: Hepatic nuclear factor 4 (HNF4) is a transcription factor whose expression is crucial for mouse embryonic development, for liver-specific gene expression and for the prevention of one form of maturity-onset diabetes of the young. Its domain structure has been defined previously and is similar to other members of the nuclear receptor superfamily. A repressor domain has now been localised to a region of 14 amino acids (residues 428-441) near the C-terminus of HNF4 and is sufficient by itself to repress the activity of the activation function 2 (AF2) domain. Multiple mutations within this repressor domain enhance activity. Interestingly, this repressor domain shares homology with a repressor domain in the progesterone receptor. In a detailed mutagenesis study of the AF2 core, we demonstrate that L 366, which is conserved in the AF2 core between HNF4 and a number of orphan nuclear receptors, is essential for the full activity of the AF2 domain. Furthermore, a double mutation of E 363 and L 366 suggests that these residues might act in a cooperative manner.
authors.affiliation: Chemical Pathology Unit, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: V P
authors.initials: VP
authors.lastname: Iyemere
authors.forename: N H
authors.initials: NH
authors.lastname: Davies
authors.forename: G G
authors.initials: GG
authors.lastname: Brownlee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011392:Proline; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D011392:Proline