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Communication between the ERRalpha homodimer interface and the PGC-1alpha binding surface via the helix 8-9 loop.

Abstract : Although structural studies on the ligand-binding domain (LBD) have established the general mode of nuclear receptor (NR)/coactivator interaction, determinants of binding specificity are only partially understood. The LBD of estrogen receptor-alpha (ERalpha), for example, interacts only with a region of peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, which contains the canonical LXXLL motif (NR box2), whereas the LBD of estrogen-related receptor-alpha (ERRalpha) also binds efficiently an untypical, LXXYL-containing region (NR box3) of PGC-1alpha. Surprisingly, in a previous structural study, the ERalpha LBD has been observed to bind NR box3 of transcriptional intermediary factor (TIF)-2 untypically via LXXYL, whereas the ERRalpha LBD binds this region of TIF-2 only poorly. Here we present a new crystal structure of the ERRalpha LBD in complex with a PGC-1alpha box3 peptide. In this structure, residues N-terminal of the PGC-1alpha LXXYL motif formed contacts with helix 4, the loop connecting helices 8 and 9, and with the C terminus of the ERRalpha LBD. Interaction studies using wild-type and mutant PGC-1alpha and ERRalpha showed that these contacts are functionally relevant and are required for efficient ERRalpha/PGC-1alpha interaction. Furthermore, a structure comparison between ERRalpha and ERalpha and mutation analyses provided evidence that the helix 8-9 loop, which differs significantly in both nuclear receptors, is a major determinant of coactivator binding specificity. Finally, our results revealed that in ERRalpha the helix 8-9 loop allosterically links the LBD homodimer interface with the coactivator cleft, thus providing a plausible explanation for distinct PGC-1alpha binding to ERRalpha monomers and homodimers.
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https://www.hal.inserm.fr/inserm-00311104
Contributor : Maité Peney <>
Submitted on : Tuesday, August 12, 2008 - 5:17:29 PM
Last modification on : Friday, September 11, 2020 - 2:38:42 PM

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Holger Greschik, Magnus Althage, Ralf Flaig, Yoshiteru Sato, Virginie Chavant, et al.. Communication between the ERRalpha homodimer interface and the PGC-1alpha binding surface via the helix 8-9 loop.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2008, 283 (29), pp.20220-30. ⟨10.1074/jbc.M801920200⟩. ⟨inserm-00311104⟩

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