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Nucleic Acids Research, 2003, Vol. 31, No. 22 6640-6650
© 2003 Oxford University Press

Article

Critical role of charged residues in helix 7 of the ligand binding domain in Hepatocyte Nuclear Factor 4{alpha} dimerisation and transcriptional activity

Jérôme Eeckhoute, Bénédicte Oxombre, Pierre Formstecher, Philippe Lefebvre and Bernard Laine*

INSERM U459, Faculté de Médecine Henri Warembourg, 1 Place de Verdun, F-59045 Lille Cedex, France

*To whom correspondence should be addressed. Tel: +33 03 20 62 69 51; Fax: +33 03 20 62 68 84; Email: blaine{at}lille.inserm.fr

Hepatocyte Nuclear Factor 4{alpha} (HNF4{alpha}, NR2A1) is central to hepatocyte and pancreatic ß-cell functions. Along with retinoid X receptor {alpha} (RXR{alpha}), HNF4{alpha} belongs to the nuclear receptor subfamily 2 (NR2), characterised by a conserved arginyl residue and a glutamate residue insert in helix 7 (H7) of the ligand binding domain (LBD). Crystallographic studies indicate that R348 and E352 residues in RXR{alpha} H7 are involved in charge-driven interactions that improve dimerisation. Consistent with these findings, we showed that removing the charge of the corresponding residues in HNF4{alpha} H7, R258 and E262, impaired dimerisation in solution. Moreover, our results provide a new concept according to which helices of the HNF4{alpha} LBD dimerisation interface contribute differently to dimerisation required for DNA binding; unlike H9 and H10, H7 is not involved in DNA binding. Substitutions of E262 decreased the repression of HNF4{alpha} transcriptional activity by a dominant-negative HNF4{alpha} mutant, highlighting the importance of this residue for dimerisation in the cell context. The E262 insert is crucial for HNF4{alpha} function since its deletion abolished HNF4{alpha} transcriptional activity and coactivator recruitment. The glutamate residue insert and the conserved arginyl residue in H7 most probably represent a signature of the NR2 subfamily of nuclear receptors.


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J. Eeckhoute, P. Formstecher, and B. Laine
Hepatocyte Nuclear Factor 4{alpha} enhances the Hepatocyte Nuclear Factor 1{alpha}-mediated activation of transcription
Nucleic Acids Res., May 11, 2004; 32(8): 2586 - 2593.
[Abstract] [Full Text] [PDF]


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