Functional characterization of hepatocyte nuclear factor-4 alpha dimerization interface mutants

The FEBS Journal
Eleni AggelidouMargarita Hadzopoulou-Cladaras

Abstract

Hepatocyte nuclear factor-4 (HNF-4alpha), a member of the nuclear receptor superfamily, binds DNA exclusively as a homodimer. Dimerization controls important aspects of receptor function, such as DNA binding, protein stability, ligand binding and interaction with coactivators. Crystallographic data of the HNF-4alpha ligand-binding domain (LBD) demonstrated that the homodimer interface is composed of residues in helices 7, 9 and 10 with intermolecular salt bridges, hydrogen bonds and hydrophobic interactions contributing to the stability of the interface. To investigate the importance of the proposed ionic interactions for HNF-4alpha dimerization, interactions critical for formation of the LBD homodimer interface were disrupted by introducing point mutations in residues D261N (H7), E269Q (H7), Q307L (H9), D312N (H9) and Q336L (H10). Mutants were analysed for transactivation, coactivator interaction, DNA binding and dimerization. EMSA analysis showed that the mutants are able to bind DNA as dimers and coimmunoprecipitation assays confirmed dimerization in solution. Furthermore, the mutations do not compromise HNF-4alpha activity and are responsive to PPAR-gamma coactivator-1 (PGC-1). Finally, residue R324, located in the H9/H10 l...Continue Reading

References

Jan 3, 1997·The Journal of Biological Chemistry·M Hadzopoulou-CladarasJ A Ladias
Sep 20, 2000·Journal of Molecular Biology·A A BoganF M Sladek
Aug 24, 2002·The Journal of Biological Chemistry·Sirano Dhe-PaganonSteven E Shoelson
Jun 13, 2003·Proceedings of the National Academy of Sciences of the United States of America·Ernie de BoerJohn Strouboulis
May 5, 2004·The Journal of Biological Chemistry·Eleni AggelidouMargarita Hadzopoulou-Cladaras
Apr 14, 2005·The Journal of Biological Chemistry·Panagiota IordanidouMargarita Hadzopoulou-Cladaras

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Citations

Apr 21, 2020·The FEBS Journal

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