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

DOI: 10.1074/jbc.M801920200 DOI Help

Authors: Holger Greschik (University of Freiburg) , Magnus Althage (Astra Zeneca,Moelndal) , Ralf Flaig (Diamond Light Source) , Yoshiteru Sato (Institut de Génétique et de Biologie Moléculaire et Cellulaire) , Virginie Chavant (Institut de Génétique et de Biologie Moléculaire et Cellulaire) , Carole Peluso-iltis (IGBMC) , Laurence Choulier (University of Strasbourg) , Philippe Cronet (Astra Zeneca) , Natacha Rochel (IGBMC,Strasbourg) , Roland Schüle (University of Freiburg) , Per-erik P.e. Strömstedt (Astra Zeneca,Moelndal) , Dino Moras (IGBMC,Strasbourg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 283 (29) , PAGES 20220-20230

State: Published (Approved)
Published: July 2008

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-? (ER?), for example, interacts only with a region of peroxisome proliferator-activated receptor coactivator (PGC)-1?, which contains the canonical LXXLL motif (NR box2), whereas the LBD of estrogen-related receptor-? (ERR?) also binds efficiently an untypical, LXXYL-containing region (NR box3) of PGC-1?. Surprisingly, in a previous structural study, the ER? LBD has been observed to bind NR box3 of transcriptional intermediary factor (TIF)-2 untypically via LXXYL, whereas the ERR? LBD binds this region of TIF-2 only poorly. Here we present a new crystal structure of the ERR? LBD in complex with a PGC-1? box3 peptide. In this structure, residues N-terminal of the PGC-1? LXXYL motif formed contacts with helix 4, the loop connecting helices 8 and 9, and with the C terminus of the ERR? LBD. Interaction studies using wild-type and mutant PGC-1? and ERR? showed that these contacts are functionally relevant and are required for efficient ERR?/PGC-1? interaction. Furthermore, a structure comparison between ERR? and ER? 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 ERR? the helix 8–9 loop allosterically links the LBD homodimer interface with the coactivator cleft, thus providing a plausible explanation for distinct PGC-1? binding to ERR? monomers and homodimers.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: NONE-No attached Diamond beamline