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This version published online on June 3, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0375
A more recent version of this article appeared on September 1, 2004
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Submitted on September 26, 2003
Accepted on May 28, 2004

Distinct Recognition Modes of FXXLF and LXXLL Motifs by the Androgen Receptor

Hendrikus J. Dubbink*, Remko Hersmus, Chandra S. Verma, Hetty A.G.M. van der Korput, Cor A. Berrevoets, Judith van Tol, Angelique C.J. Ziel-van der Made, Albert O. Brinkmann, Ashley C.W. Pike, and Jan Trapman

Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands and Department of Reproduction and Development, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands and Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, United Kingdom

* To whom correspondence should be addressed. E-mail: h.dubbink{at}erasmusmc.nl.

Among nuclear receptors, the androgen receptor (AR) is unique in that its ligand-binding domain (LBD) interacts with the FXXLF motif in the N-terminal domain, resembling coactivator LXXLL motifs. We compared AR- and estrogen receptor {alpha} (ER{alpha})-LBD interactions of the wild type AR FXXLF motif and coactivator TIF2 LXXLL motifs and variants of these motifs. Random mutagenesis revealed a key role for the F residues in FXXLF motifs in high affinity and selective AR LBD interaction. The FXXLF motif in full-length AR and TIF2 LXXLL motifs competed for an overlapping binding site. A computer model of the AR LBD/AR FXXLF complex showed that the bulky F residues are buried in a deep coactivator-binding groove. The corresponding groove in ER{alpha} LBD is considerably shallower, explaining lack of binding of any of the FXXLF motifs tested. FXXLF and LXXLL motif interaction depended on different charged amino acid residues in the AR LBD present at opposite ends of the coactivator groove. In conclusion, our data demonstrate the importance of a deep hydrophobic groove and alternative usage of charged amino acids in specifying peptide binding to the AR LBD.
Key words: androgen receptor • coactivator-binding groove • FXXLF motif • LXXLL motif • nuclear receptor

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  AR
Coregulators:   GRIP1
Ligands:   17β-Estradiol  |  Dihydrotestosterone  |  R1881



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