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Structural basis for the cell-specific activities of the NGFI-B and the Nurr1 ligand-binding domain

DOI: 10.1074/jbc.M413175200 DOI Help
PMID: 15716272 PMID Help

Authors: Ralf Flaig (Diamond Light Source) , Holer Greschik (University of Freiburg) , Carole Peluso-iltis (IGBMC, Illkirch) , Dino Moras (IGBMC, Illkirch)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 280 (19) , PAGES 19250-19258

State: Published (Approved)
Published: February 2005

Abstract: 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.

Journal Keywords: Nuclear Receptors; Transcription; Ligand

Subject Areas: Biology and Bio-materials

Facility: ESRF, SLS

Added On: 19/04/2010 18:20

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