Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus.

Abstract	The androgen receptor (AR) regulates male sexual development. We have now investigated AR homodimerization, hormone-dependent monomerization and nuclear translocation in PC-3 and COS-1 cells, by utilizing mutations associated with the androgen insensitivity syndrome: Pro767Ala, Phe765Leu, Met743Val and Trp742Arg. AR wild type (WT) was expressed as a homodimer in the cytoplasm, while none of these mutants formed homodimers. Unlike AR WT which responded to 1 nM dihydrotestosterone (DHT) to dissociate and translocate into the nucleus, AR Pro767Ala and Phe765Leu mutants remain as the monomer in the cytoplasm. In the crystal structure of the AR LBD homodimer, Pro767 and Phe765 reside closely on a loop that constitutes the dimer interface; their sidechains interact with the Pro767 of the other monomer and with the DHT molecule in the ligand-binding pocket. These observations place Phe765 at a position to facilitate DHT binding to Pro767 and lead to dissociation of the AR homodimer in the cytoplasm. This Pro-Phe Met relay may constitute a structural switch that mediates androgen signaling and is conserved in other steroid hormone receptors.
Authors	Ryota Shizu, Kosuke Yokobori, Lalith Perera, Lee Pedersen, Masahiko Negishi
Journal	Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 16734 (11 13 2019) ISSN: 2045-2322 [Electronic] England
PMID	31723170 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References	AR protein, human Androgens Ligands Receptors, Androgen Dihydrotestosterone
Topics	Androgens (metabolism) Animals COS Cells Cell Nucleus (metabolism) Chlorocebus aethiops Cytoplasm (metabolism) Dihydrotestosterone (metabolism) Humans Ligands Male Mutation Prostatic Neoplasms (metabolism, pathology) Protein Conformation Protein Multimerization Protein Transport Receptors, Androgen (chemistry, genetics, metabolism) Signal Transduction Tumor Cells, Cultured

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