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• W2017391693 abstract "The nuclear receptor hepatocyte nuclear factor 4 (HNF-4) is an important regulator of several genes involved in diverse metabolic and developmental pathways. Mutations in the HNF-4Agene are responsible for the maturity-onset diabetes of the young type 1. Recently, we showed that the 24 N-terminal residues of HNF-4 function as an acidic transcriptional activator, termed AF-1 (Hadzopoulou-Cladaras, M., Kistanova, E., Evagelopoulou, C., Zeng, S., Cladaras C., and Ladias, J. A. A. (1997) J. Biol. Chem. 272, 539–550). To identify the critical residues for this activator, we performed an extensive genetic analysis using site-directed mutagenesis. We showed that the aromatic and bulky hydrophobic residues Tyr6, Tyr14, Phe19, Lys10, and Lys17 are essential for AF-1 function. To a lesser degree, five acidic residues are also important for optimal activity. Positional changes of Tyr6 and Tyr14 reduced AF-1 activity, underscoring the importance of primary structure for this activator. Our analysis also indicated that AF-1 is bipartite, consisting of two modules that synergize to activate transcription. More important, AF-1 shares common structural motifs and molecular targets with the activators of the tumor suppressor protein p53 and NF-κB-p65, suggesting similar mechanisms of action. Remarkably, AF-1 interacted specifically with multiple transcriptional targets, including the TATA-binding protein; the TATA-binding protein-associated factors TAFII31 and TAFII80; transcription factor IIB; transcription factor IIH-p62; and the coactivators cAMP-responsive element-binding protein-binding protein, ADA2, and PC4. The interaction of AF-1 with proteins that regulate distinct steps of transcription may provide a mechanism for synergistic activation of gene expression by AF-1. The nuclear receptor hepatocyte nuclear factor 4 (HNF-4) is an important regulator of several genes involved in diverse metabolic and developmental pathways. Mutations in the HNF-4Agene are responsible for the maturity-onset diabetes of the young type 1. Recently, we showed that the 24 N-terminal residues of HNF-4 function as an acidic transcriptional activator, termed AF-1 (Hadzopoulou-Cladaras, M., Kistanova, E., Evagelopoulou, C., Zeng, S., Cladaras C., and Ladias, J. A. A. (1997) J. Biol. Chem. 272, 539–550). To identify the critical residues for this activator, we performed an extensive genetic analysis using site-directed mutagenesis. We showed that the aromatic and bulky hydrophobic residues Tyr6, Tyr14, Phe19, Lys10, and Lys17 are essential for AF-1 function. To a lesser degree, five acidic residues are also important for optimal activity. Positional changes of Tyr6 and Tyr14 reduced AF-1 activity, underscoring the importance of primary structure for this activator. Our analysis also indicated that AF-1 is bipartite, consisting of two modules that synergize to activate transcription. More important, AF-1 shares common structural motifs and molecular targets with the activators of the tumor suppressor protein p53 and NF-κB-p65, suggesting similar mechanisms of action. Remarkably, AF-1 interacted specifically with multiple transcriptional targets, including the TATA-binding protein; the TATA-binding protein-associated factors TAFII31 and TAFII80; transcription factor IIB; transcription factor IIH-p62; and the coactivators cAMP-responsive element-binding protein-binding protein, ADA2, and PC4. The interaction of AF-1 with proteins that regulate distinct steps of transcription may provide a mechanism for synergistic activation of gene expression by AF-1. general transcription factors transcription factor DNA-binding domain TATA-binding protein TATA-binding protein-associated factor cAMP-responsive element-binding protein-binding protein glucocorticoid receptor hepatocyte nuclear factor 4 glutathione S-transferase polymerase chain reaction hemagglutinin polyacrylamide gel electrophoresis. Transcription initiation at RNA polymerase II promoters involves the assembly of a basal transcription complex containing RNA polymerase II and general transcription factors (GTFs),1 including TFIIA, -B, -D, -E, -F, and -H (1Roeder R.G. Trends Biochem. Sci. 1996; 21: 327-335Abstract Full Text PDF PubMed Scopus (718) Google Scholar). Stimulation of transcription is directed by sequence-specific DNA-binding proteins, termed activators. Typically, activators are modular, containing a DNA-binding domain (DBD) and one or more activation domains that increase the rate of transcription through interactions with other proteins. It is believed that activators recruit chromatin-remodeling proteins and GTFs to the promoter, relieving the repressive effect of chromatin on transcription and affecting the initiation, promoter clearance, and elongation of transcription (1Roeder R.G. Trends Biochem. Sci. 1996; 21: 327-335Abstract Full Text PDF PubMed Scopus (718) Google Scholar, 2Triezenberg S.J. Curr. Opin. Genet. Dev. 1995; 5: 190-196Crossref PubMed Scopus (348) Google Scholar, 3Bentley D.L. Curr. Opin. Genet. Dev. 1995; 5: 210-216Crossref PubMed Scopus (104) Google Scholar). Activation domains are classified according to their predominant amino acid composition into proline-rich, glutamine-rich, serine/threonine-rich, and acidic activators. However, the structural requirements and mechanisms of function of these activators remain poorly understood.A hallmark of acidic activators is their ability to function universally in all eukaryotes tested, implying that their targets and mechanisms of action have been highly conserved through evolution (2Triezenberg S.J. Curr. Opin. Genet. Dev. 1995; 5: 190-196Crossref PubMed Scopus (348) Google Scholar,4Hahn S. Cell. 1993; 72: 481-483Abstract Full Text PDF PubMed Scopus (120) Google Scholar). Several GTFs are molecular targets of acidic activators and are important for their function. Examples include TBP, TFIIB, TFIIH-p62, TAFII31, and TAFII80, which interact with the activators of the herpes simplex virus-1 virion protein VP16 (5Roberts S.G.E. Ha I. Maldonado E. Reinberg D. Green M.R. Nature. 1993; 363: 741-744Crossref PubMed Scopus (179) Google Scholar, 6Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar, 7Klemm R.D. Goodrich J.A. Zhou S. Tjian R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5788-5792Crossref PubMed Scopus (106) Google Scholar), p53 (6Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar, 8Liu X. Miller C.W. Koeffler P.H. Berk A.J. Mol. Cell. Biol. 1993; 13: 3291-3300Crossref PubMed Scopus (232) Google Scholar, 9Thut C.J. Chen J.-L. Klemm R. Tjian R. Science. 1995; 267: 100-104Crossref PubMed Scopus (406) Google Scholar), and NF-κB-p65 (10Hisatake K. Ohta T. Takada R. Guermah M. Horikoshi M. Nakatani Y. Roeder R.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8195-8199Crossref PubMed Scopus (70) Google Scholar). These activators also interact with coactivators, including CBP (11Gerritsen M.E. Williams A.J. Neish A.S. Moore S. Shi Y. Collins T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2927-2932Crossref PubMed Scopus (710) Google Scholar, 12Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar), ADA2 (13Barlev N.A. Candau R. Wang L. Darpino P. Silverman N. Berger S.L. J. Biol. Chem. 1995; 270: 19337-19344Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar), and PC4 (14Ge H. Roeder R.G. Cell. 1994; 78: 513-523Abstract Full Text PDF PubMed Scopus (306) Google Scholar). Thus, acidic activators interact with many proteins to achieve transcriptional activation.An emerging theme from mutagenesis studies of acidic activation domains, including those of VP16 (15Cress W.D. Triezenberg S.J. Science. 1991; 251: 87-90Crossref PubMed Scopus (323) Google Scholar, 16Regier J.L. Shen F. Triezenberg S.J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 883-887Crossref PubMed Scopus (224) Google Scholar), p53 (17Lin J. Chen J. Elenbaas B. Levine A.J. Genes Dev. 1994; 8: 1235-1246Crossref PubMed Scopus (577) Google Scholar), NF-κB-p65 (18Blair W.S. Bogerd H.P. Madore S.J. Cullen B.R. Mol. Cell. Biol. 1994; 14: 7226-7234Crossref PubMed Scopus (100) Google Scholar), and the glucocorticoid receptor (GR) (19Almlof T. Gustafsson J.-A. Wright A.P.H. Mol. Cell. Biol. 1997; 17: 934-945Crossref PubMed Scopus (62) Google Scholar), is that aromatic and hydrophobic residues are essential for activity. In contrast, negative charge, although important for function, is not sufficient. Furthermore, several activation domains, including those of VP16 and NF-κB-p65, consist of short modules that act synergistically to activate transcription (16Regier J.L. Shen F. Triezenberg S.J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 883-887Crossref PubMed Scopus (224) Google Scholar, 18Blair W.S. Bogerd H.P. Madore S.J. Cullen B.R. Mol. Cell. Biol. 1994; 14: 7226-7234Crossref PubMed Scopus (100) Google Scholar). From a structural perspective, however, the molecular basis of acidic activator action remains obscure (4Hahn S. Cell. 1993; 72: 481-483Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 6Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar). Several contradictory models proposed that these activators function as amphipathic α-helices (20Giniger E. Ptashne M. Nature. 1987; 330: 670-672Crossref PubMed Scopus (222) Google Scholar), β-sheets (21Van Hoy M. Leuther K.K. Kodadek T. Johnston S.A. Cell. 1993; 72: 587-594Abstract Full Text PDF PubMed Scopus (121) Google Scholar), or unstructured domains (22Sigler P.B. Nature. 1988; 333: 210-212Crossref PubMed Scopus (291) Google Scholar). However, recent studies support the α-helical model. First, the crystal structure of the p53 activator bound to the MDM2 oncoprotein revealed that this activator forms an amphipathic α-helix (23Kussie P.H. Gorina S. Marechal V. Elenbaas B. Moreau J. Levine A.J. Pavletich N.P. Science. 1996; 274: 948-953Crossref PubMed Scopus (1758) Google Scholar). The prominent feature of the p53 interaction interface is a set of three aromatic/hydrophobic residues (Phe19, Trp23, and Leu26) that insert into a hydrophobic cleft of MDM2. Since the same amino acids are critical for transactivation (17Lin J. Chen J. Elenbaas B. Levine A.J. Genes Dev. 1994; 8: 1235-1246Crossref PubMed Scopus (577) Google Scholar), it was suggested that this domain of p53 may activate transcription also as an α-helix, with its hydrophobic residues contacting GTFs (23Kussie P.H. Gorina S. Marechal V. Elenbaas B. Moreau J. Levine A.J. Pavletich N.P. Science. 1996; 274: 948-953Crossref PubMed Scopus (1758) Google Scholar). Second, nuclear magnetic resonance studies showed that the VP16 activator undergoes an induced transition from random coil to α-helix upon interaction with TAFII31 (24Uesugi M. Nyanguile O. Lu H. Levine A.J. Verdine G.L. Science. 1997; 277: 1310-1313Crossref PubMed Scopus (270) Google Scholar). Thus, an induced amphipathic α-helix may be a common structural feature of acidic activators. Additional structural and functional studies of acidic activators are essential for identification of the specificity determinants in these domains and elucidation of their mechanisms of action.We recently reported that the 24 N-terminal residues of the nuclear receptor HNF-4 constitute an autonomous acidic activator, termed AF-1 (activation function-1) (25Hadzopoulou-Cladaras M. Kistanova E. Evagelopoulou C. Zeng S. Cladaras C. Ladias J.A.A. J. Biol. Chem. 1997; 272: 539-550Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Deletion of AF-1 results in 40% reduction of the HNF-4-mediated activation (25Hadzopoulou-Cladaras M. Kistanova E. Evagelopoulou C. Zeng S. Cladaras C. Ladias J.A.A. J. Biol. Chem. 1997; 272: 539-550Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), indicating that this activation domain plays a central role in the function of this nuclear receptor. HNF-4 is an important regulator of several genes involved in diverse metabolic pathways, including the genes for apolipoproteins A-II, B, and C-III (26Ladias J.A.A. Hadzopoulou-Cladaras M. Kardassis D. Cardot P. Cheng J. Zannis V. Cladaras C. J. Biol. Chem. 1992; 267: 15849-15860Abstract Full Text PDF PubMed Google Scholar) and human immunodeficiency virus-1 (27Ladias J.A.A. J. Biol. Chem. 1994; 269: 5944-5951Abstract Full Text PDF PubMed Google Scholar). Moreover, mutations in theHNF-4A gene are responsible for the maturity-onset diabetes of the young type 1, an autosomal dominant early-onset form of non-insulin-dependent diabetes mellitus (28Yamagata K. Furuta H. Oda N. Kaisaki P.J. Menzel S. Cox N.J. Fajans S.S. Signorini S. Stoffel M. Bell G.I. Nature. 1996; 384: 458-460Crossref PubMed Scopus (1041) Google Scholar). Therefore, investigations into the mode of action of the HNF-4 activation domains are important for our understanding of the basic mechanisms of gene expression by this nuclear receptor and the pathogenesis of several metabolic diseases, including diabetes.In this study, we have performed a systematic structure-function analysis of HNF-4 AF-1 to identify the critical amino acids and molecular targets that mediate its function. We show that aromatic and bulky hydrophobic residues are essential for AF-1 transactivation, whereas acidic residues are not sufficient for activity. We also demonstrate that AF-1 shares common structural motifs and molecular targets with the activation domains of p53, NF-κB-p65, and VP16, implying that these activators may function through common mechanisms. Remarkably, AF-1 interacts with multiple proteins that act at distinct steps during transcription, providing a possible mechanism for the functional synergy exhibited by this activator in vivo. Transcription initiation at RNA polymerase II promoters involves the assembly of a basal transcription complex containing RNA polymerase II and general transcription factors (GTFs),1 including TFIIA, -B, -D, -E, -F, and -H (1Roeder R.G. Trends Biochem. Sci. 1996; 21: 327-335Abstract Full Text PDF PubMed Scopus (718) Google Scholar). Stimulation of transcription is directed by sequence-specific DNA-binding proteins, termed activators. Typically, activators are modular, containing a DNA-binding domain (DBD) and one or more activation domains that increase the rate of transcription through interactions with other proteins. It is believed that activators recruit chromatin-remodeling proteins and GTFs to the promoter, relieving the repressive effect of chromatin on transcription and affecting the initiation, promoter clearance, and elongation of transcription (1Roeder R.G. Trends Biochem. Sci. 1996; 21: 327-335Abstract Full Text PDF PubMed Scopus (718) Google Scholar, 2Triezenberg S.J. Curr. Opin. Genet. Dev. 1995; 5: 190-196Crossref PubMed Scopus (348) Google Scholar, 3Bentley D.L. Curr. Opin. Genet. Dev. 1995; 5: 210-216Crossref PubMed Scopus (104) Google Scholar). Activation domains are classified according to their predominant amino acid composition into proline-rich, glutamine-rich, serine/threonine-rich, and acidic activators. However, the structural requirements and mechanisms of function of these activators remain poorly understood. A hallmark of acidic activators is their ability to function universally in all eukaryotes tested, implying that their targets and mechanisms of action have been highly conserved through evolution (2Triezenberg S.J. Curr. Opin. Genet. Dev. 1995; 5: 190-196Crossref PubMed Scopus (348) Google Scholar,4Hahn S. Cell. 1993; 72: 481-483Abstract Full Text PDF PubMed Scopus (120) Google Scholar). Several GTFs are molecular targets of acidic activators and are important for their function. Examples include TBP, TFIIB, TFIIH-p62, TAFII31, and TAFII80, which interact with the activators of the herpes simplex virus-1 virion protein VP16 (5Roberts S.G.E. Ha I. Maldonado E. Reinberg D. Green M.R. Nature. 1993; 363: 741-744Crossref PubMed Scopus (179) Google Scholar, 6Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar, 7Klemm R.D. Goodrich J.A. Zhou S. Tjian R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5788-5792Crossref PubMed Scopus (106) Google Scholar), p53 (6Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar, 8Liu X. Miller C.W. Koeffler P.H. Berk A.J. Mol. Cell. Biol. 1993; 13: 3291-3300Crossref PubMed Scopus (232) Google Scholar, 9Thut C.J. Chen J.-L. Klemm R. Tjian R. Science. 1995; 267: 100-104Crossref PubMed Scopus (406) Google Scholar), and NF-κB-p65 (10Hisatake K. Ohta T. Takada R. Guermah M. Horikoshi M. Nakatani Y. Roeder R.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8195-8199Crossref PubMed Scopus (70) Google Scholar). These activators also interact with coactivators, including CBP (11Gerritsen M.E. Williams A.J. Neish A.S. Moore S. Shi Y. Collins T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2927-2932Crossref PubMed Scopus (710) Google Scholar, 12Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar), ADA2 (13Barlev N.A. Candau R. Wang L. Darpino P. Silverman N. Berger S.L. J. Biol. Chem. 1995; 270: 19337-19344Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar), and PC4 (14Ge H. Roeder R.G. Cell. 1994; 78: 513-523Abstract Full Text PDF PubMed Scopus (306) Google Scholar). Thus, acidic activators interact with many proteins to achieve transcriptional activation. An emerging theme from mutagenesis studies of acidic activation domains, including those of VP16 (15Cress W.D. Triezenberg S.J. Science. 1991; 251: 87-90Crossref PubMed Scopus (323) Google Scholar, 16Regier J.L. Shen F. Triezenberg S.J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 883-887Crossref PubMed Scopus (224) Google Scholar), p53 (17Lin J. Chen J. Elenbaas B. Levine A.J. Genes Dev. 1994; 8: 1235-1246Crossref PubMed Scopus (577) Google Scholar), NF-κB-p65 (18Blair W.S. Bogerd H.P. Madore S.J. Cullen B.R. Mol. Cell. Biol. 1994; 14: 7226-7234Crossref PubMed Scopus (100) Google Scholar), and the glucocorticoid receptor (GR) (19Almlof T. Gustafsson J.-A. Wright A.P.H. Mol. Cell. Biol. 1997; 17: 934-945Crossref PubMed Scopus (62) Google Scholar), is that aromatic and hydrophobic residues are essential for activity. In contrast, negative charge, although important for function, is not sufficient. Furthermore, several activation domains, including those of VP16 and NF-κB-p65, consist of short modules that act synergistically to activate transcription (16Regier J.L. Shen F. Triezenberg S.J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 883-887Crossref PubMed Scopus (224) Google Scholar, 18Blair W.S. Bogerd H.P. Madore S.J. Cullen B.R. Mol. Cell. Biol. 1994; 14: 7226-7234Crossref PubMed Scopus (100) Google Scholar). From a structural perspective, however, the molecular basis of acidic activator action remains obscure (4Hahn S. Cell. 1993; 72: 481-483Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 6Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar). Several contradictory models proposed that these activators function as amphipathic α-helices (20Giniger E. Ptashne M. Nature. 1987; 330: 670-672Crossref PubMed Scopus (222) Google Scholar), β-sheets (21Van Hoy M. Leuther K.K. Kodadek T. Johnston S.A. Cell. 1993; 72: 587-594Abstract Full Text PDF PubMed Scopus (121) Google Scholar), or unstructured domains (22Sigler P.B. Nature. 1988; 333: 210-212Crossref PubMed Scopus (291) Google Scholar). However, recent studies support the α-helical model. First, the crystal structure of the p53 activator bound to the MDM2 oncoprotein revealed that this activator forms an amphipathic α-helix (23Kussie P.H. Gorina S. Marechal V. Elenbaas B. Moreau J. Levine A.J. Pavletich N.P. Science. 1996; 274: 948-953Crossref PubMed Scopus (1758) Google Scholar). The prominent feature of the p53 interaction interface is a set of three aromatic/hydrophobic residues (Phe19, Trp23, and Leu26) that insert into a hydrophobic cleft of MDM2. Since the same amino acids are critical for transactivation (17Lin J. Chen J. Elenbaas B. Levine A.J. Genes Dev. 1994; 8: 1235-1246Crossref PubMed Scopus (577) Google Scholar), it was suggested that this domain of p53 may activate transcription also as an α-helix, with its hydrophobic residues contacting GTFs (23Kussie P.H. Gorina S. Marechal V. Elenbaas B. Moreau J. Levine A.J. Pavletich N.P. Science. 1996; 274: 948-953Crossref PubMed Scopus (1758) Google Scholar). Second, nuclear magnetic resonance studies showed that the VP16 activator undergoes an induced transition from random coil to α-helix upon interaction with TAFII31 (24Uesugi M. Nyanguile O. Lu H. Levine A.J. Verdine G.L. Science. 1997; 277: 1310-1313Crossref PubMed Scopus (270) Google Scholar). Thus, an induced amphipathic α-helix may be a common structural feature of acidic activators. Additional structural and functional studies of acidic activators are essential for identification of the specificity determinants in these domains and elucidation of their mechanisms of action. We recently reported that the 24 N-terminal residues of the nuclear receptor HNF-4 constitute an autonomous acidic activator, termed AF-1 (activation function-1) (25Hadzopoulou-Cladaras M. Kistanova E. Evagelopoulou C. Zeng S. Cladaras C. Ladias J.A.A. J. Biol. Chem. 1997; 272: 539-550Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Deletion of AF-1 results in 40% reduction of the HNF-4-mediated activation (25Hadzopoulou-Cladaras M. Kistanova E. Evagelopoulou C. Zeng S. Cladaras C. Ladias J.A.A. J. Biol. Chem. 1997; 272: 539-550Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), indicating that this activation domain plays a central role in the function of this nuclear receptor. HNF-4 is an important regulator of several genes involved in diverse metabolic pathways, including the genes for apolipoproteins A-II, B, and C-III (26Ladias J.A.A. Hadzopoulou-Cladaras M. Kardassis D. Cardot P. Cheng J. Zannis V. Cladaras C. J. Biol. Chem. 1992; 267: 15849-15860Abstract Full Text PDF PubMed Google Scholar) and human immunodeficiency virus-1 (27Ladias J.A.A. J. Biol. Chem. 1994; 269: 5944-5951Abstract Full Text PDF PubMed Google Scholar). Moreover, mutations in theHNF-4A gene are responsible for the maturity-onset diabetes of the young type 1, an autosomal dominant early-onset form of non-insulin-dependent diabetes mellitus (28Yamagata K. Furuta H. Oda N. Kaisaki P.J. Menzel S. Cox N.J. Fajans S.S. Signorini S. Stoffel M. Bell G.I. Nature. 1996; 384: 458-460Crossref PubMed Scopus (1041) Google Scholar). Therefore, investigations into the mode of action of the HNF-4 activation domains are important for our understanding of the basic mechanisms of gene expression by this nuclear receptor and the pathogenesis of several metabolic diseases, including diabetes. In this study, we have performed a systematic structure-function analysis of HNF-4 AF-1 to identify the critical amino acids and molecular targets that mediate its function. We show that aromatic and bulky hydrophobic residues are essential for AF-1 transactivation, whereas acidic residues are not sufficient for activity. We also demonstrate that AF-1 shares common structural motifs and molecular targets with the activation domains of p53, NF-κB-p65, and VP16, implying that these activators may function through common mechanisms. Remarkably, AF-1 interacts with multiple proteins that act at distinct steps during transcription, providing a possible mechanism for the functional synergy exhibited by this activator in vivo. We thank Jian Cheng for technical assistance during the initial phase of this study. We are also grateful to Drs. Shelley Berger, Tucker Collins, Richard Goodman, Jack Greenblatt, Danny Reinberg, Robert Roeder, and Robert Tjian for kindly providing gene constructs." @default.
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• W2017391693 title "Critical Structural Elements and Multitarget Protein Interactions of the Transcriptional Activator AF-1 of Hepatocyte Nuclear Factor 4" @default.
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