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

Department of Pathology (H.J.D., R.H., H.A.G.M.v.d.K., J.v.T., A.C.J.Z.-v.d.M., J.T.), Josephine Nefkens Institute, and Department of Reproduction and Development (C.A.B., A.O.B.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands; and Structural Biology Laboratory (C.S.V., A.C.W.P.), Department of Chemistry, University of York, York YO10 5DD, United Kingdom

Address all correspondence and requests for reprints to: Hendrikus J. Dubbink, Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands. 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 -LBD interactions of the wild-type AR FXXLF motif and coactivator transcriptional intermediary factor 2 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 transcriptional intermediary factor 2 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 estrogen receptor 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  AR

Coregulators:   GRIP1

Ligands:   17β-Estradiol  |  Dihydrotestosterone  |  R1881

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