3fs1 Citations

Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation.

J Biol Chem 284 35165-76 (2009)
Cited: 26 times
EuropePMC logo PMID: 19846556

Abstract

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4alpha interacts, peroxisome proliferation-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1alpha recruitment, we have determined the crystal structure of HNF4alpha in complex with a fragment of PGC-1alpha containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4alpha toward the LXXLL motifs of PGC-1alpha could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.

Articles - 3fs1 mentioned but not cited (12)

  1. Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α. Li J, Inoue J, Choi JM, Nakamura S, Yan Z, Fushinobu S, Kamada H, Kato H, Hashidume T, Shimizu M, Sato R. J Biol Chem 290 24021-24035 (2015)
  2. Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation. Rha GB, Wu G, Shoelson SE, Chi YI. J Biol Chem 284 35165-35176 (2009)
  3. Caffeine-free hawk tea lowers cholesterol by reducing free cholesterol uptake and the production of very-low-density lipoprotein. Feng J, Yang J, Chang Y, Qiao L, Dang H, Luo K, Guo H, An Y, Ma C, Shao H, Tian J, Yuan Y, Xie L, Xing W, Cheng J. Commun Biol 2 173 (2019)
  4. MED25 is a mediator component of HNF4α-driven transcription leading to insulin secretion in pancreatic beta-cells. Han EH, Rha GB, Chi YI. PLoS One 7 e44007 (2012)
  5. Differential effects, on oncogenic pathway signalling, by derivatives of the HNF4 α inhibitor BI6015. Kim JH, Eom HJ, Lim G, Park S, Lee J, Nam S, Kim YH, Jeong JH. Br J Cancer 120 488-498 (2019)
  6. ErbB3-binding protein 1 (EBP1) represses HNF4α-mediated transcription and insulin secretion in pancreatic β-cells. Han EH, Singh P, Lee IK, Urrutia R, Chi YI. J Biol Chem 294 13983-13994 (2019)
  7. 6-Gingerol Ameliorates Hepatic Steatosis via HNF4α/miR-467b-3p/GPAT1 Cascade. Ahn J, Lee H, Jung CH, Ha SY, Seo HD, Kim YI, Ha T. Cell Mol Gastroenterol Hepatol 12 1201-1213 (2021)
  8. In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4α identified in maturity-onset diabetes of the young type 1. Sugawara K, Nomura K, Okada Y, Sugano A, Matsumoto M, Takarada T, Takeuchi A, Awano H, Hirota Y, Nishio H, Takaoka Y, Ogawa W. J Diabetes Investig 10 680-684 (2019)
  9. Revealing active components, action targets and molecular mechanism of Gandi capsule for treating diabetic nephropathy based on network pharmacology strategy. Zhang Q, Ye Q, Huang X, Xu A, Liu Y, Qi J, Zhang H, Zhang J. BMC Complement Med Ther 20 362 (2020)
  10. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  11. Exploring Ligand Binding Domain Dynamics in the NRs Superfamily. D'Arrigo G, Autiero I, Gianquinto E, Siragusa L, Baroni M, Cruciani G, Spyrakis F. Int J Mol Sci 23 8732 (2022)
  12. Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells. Emanuelson C, Ankenbruck N, Kumbhare R, Thomas M, Connelly C, Baktash Y, Randall G, Deiters A. J Med Chem 65 16338-16352 (2022)


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  1. Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men. Basualto-Alarcón C, Llanos P, García-Rivas G, Troncoso MF, Lagos D, Barrientos G, Estrada M. Int J Endocrinol 2021 5527973 (2021)

Articles citing this publication (13)

  1. Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha. Davison JM, Lickwar CR, Song L, Breton G, Crawford GE, Rawls JF. Genome Res 27 1195-1206 (2017)
  2. Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1α/ERRγ complex. Devarakonda S, Gupta K, Chalmers MJ, Hunt JF, Griffin PR, Van Duyne GD, Spiegelman BM. Proc Natl Acad Sci U S A 108 18678-18683 (2011)
  3. Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. de Vera IMS, Munoz-Tello P, Zheng J, Dharmarajan V, Marciano DP, Matta-Camacho E, Giri PK, Shang J, Hughes TS, Rance M, Griffin PR, Kojetin DJ. Structure 27 66-77.e5 (2019)
  4. Characterization of novel peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) isoform in human liver. Felder TK, Soyal SM, Oberkofler H, Hahne P, Auer S, Weiss R, Gadermaier G, Miller K, Krempler F, Esterbauer H, Patsch W. J Biol Chem 286 42923-42936 (2011)
  5. The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. Takacs M, Petoukhov MV, Atkinson RA, Roblin P, Ogi FX, Demeler B, Potier N, Chebaro Y, Dejaegere A, Svergun DI, Moras D, Billas IM. PLoS One 8 e67810 (2013)
  6. Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA. de Vera IMS, Zheng J, Novick S, Shang J, Hughes TS, Brust R, Munoz-Tello P, Gardner WJ, Marciano DP, Kong X, Griffin PR, Kojetin DJ. Structure 25 1506-1518.e4 (2017)
  7. A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH). Srivastava J, Robertson CL, Ebeid K, Dozmorov M, Rajasekaran D, Mendoza R, Siddiq A, Akiel MA, Jariwala N, Shen XN, Windle JJ, Subler MA, Mukhopadhyay ND, Giashuddin S, Ghosh S, Lai Z, Chen Y, Fisher PB, Salem AK, Sanyal AJ, Sarkar D. Hepatology 66 466-480 (2017)
  8. Structural insights into gene repression by the orphan nuclear receptor SHP. Zhi X, Zhou XE, He Y, Zechner C, Suino-Powell KM, Kliewer SA, Melcher K, Mangelsdorf DJ, Xu HE. Proc Natl Acad Sci U S A 111 839-844 (2014)
  9. Hepatocyte nuclear factor (HNF) 4α transactivation of cytochrome P450 (Cyp) 2d40 promoter is enhanced during pregnancy in mice. Ning M, Koh KH, Pan X, Jeong H. Biochem Pharmacol 94 46-52 (2015)
  10. Probing the effect of MODY mutations near the co-activator-binding pocket of HNF4α. Rha GB, Wu G, Chi YI. Biosci Rep 31 411-419 (2011)
  11. PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2. Frodyma DE, Troia TC, Rao C, Svoboda RA, Berg JA, Shinde DD, Thomas VC, Lewis RE, Fisher KW. Cancers (Basel) 14 4879 (2022)
  12. Predicting a Kind of Unusual Multiple-States Dimerization-Modes Transformation in Protein PD-L1 System by Computational Investigation and a Generalized Rate Theory. Zhou ZX, Zhang HX, Zheng QC. Front Chem 9 783444 (2021)
  13. Full-length transcriptomic analysis in murine and human heart reveals diversity of PGC-1α promoters and isoforms regulated distinctly in myocardial ischemia and obesity. Oehler D, Spychala A, Gödecke A, Lang A, Gerdes N, Ruas J, Kelm M, Szendroedi J, Westenfeld R. BMC Biol 20 169 (2022)