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J. Biol. Chem., Vol. 280, Issue 19, 19250-19258, May 13, 2005

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Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain^*

Ralf Flaig, Holger Greschik, Carole Peluso-Iltis, and Dino Moras¶

From the Département de Biologie et Génomique Structurales, IGBMC, CNRS/INSERM/ULP, 1 Rue Laurent Fries, B.P. 10142, Illkirch 67404, France

NGFI-B is a ligand-independent orphan nuclear receptor of the NR4A subfamily that displays important functional differences with its homolog Nurr1. In particular, the NGFI-B ligand-binding domain (LBD) exhibits only modest activity in cell lines in which the Nurr1 LBD strongly activates transcription. To gain insight into the structural basis for the distinct activation potentials, we determined the crystal structure of the NGFI-B LBD at 2.4-Å resolution. Superimposition with the Nurr1 LBD revealed a significant shift of the position of helix 12, potentially caused by conservative amino acids exchanges in helix 3 or helix 12. Replacement of the helix 11–12 region of Nurr1 with that of NGFI-B dramatically reduces the transcriptional activity of the Nurr1 LBD. Similarly, mutation of Met⁴¹⁴ in helix 3 to leucine or of Leu⁵⁹¹ in helix 12 to isoleucine (the corresponding residues found in NGFI-B) significantly affects Nurr1 transactivation. In comparison, swapping the helix 11–12 region of Nurr1 into NGFI-B results in a modest increase of activity. These observations reveal a high sensitivity of LBD activity to changes that influence helix 12 positioning. Furthermore, mutation of hydrophobic surface residues in the helix 11–12 region (outside the canonical co-activator surface constituted by helices 3, 4, and 12) severely affects Nurr1 transactivation. Together, our data suggest that a novel co-regulator surface that includes helix 11 and a specifically positioned helix 12 determine the cell type-dependent activities of the NGFI-B and the Nurr1 LBD.

Received for publication, November 22, 2004 , and in revised form, February 3, 2005.

The atomic coordinates and structure factors (code 1YJE) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Université Louis Pasteur de Strasbourg, le Centre National de la Recherche Scientifique, l'Institut National de la Santé et da la Recherche Médicale, and in part by a Marie-Curie individual fellowship (to H. G.). The work described here was funded by the European Commission as SPINE, contract number QLG2-CT-2002–00988, under the RTD program "Quality of Life and Management of Living Resources." The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors contributed equally to this work.

Present address: Diamond Light Source Ltd., Rutherford Appleton Laboratory, Chilton, Didcot, Oxon OX11 0QX, United Kingdom.

^¶ To whom correspondence should be addressed. Tel.: 33-3-88-65-32-20; Fax: 33-3-88-65-32-76; E-mail: moras{at}igbmc.u-strasbg.fr.

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