RRC ID 67358
Author Shizu R, Yokobori K, Perera L, Pedersen L, Negishi M.
Title Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus.
Journal Sci Rep
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.
Volume 9(1)
Pages 16734
Published 2019-11-13
DOI 10.1038/s41598-019-53139-9
PII 10.1038/s41598-019-53139-9
PMID 31723170
PMC PMC6853983
MeSH Androgens / metabolism Animals COS Cells Cell Nucleus / metabolism* Chlorocebus aethiops Cytoplasm / metabolism* Dihydrotestosterone / metabolism* Humans Ligands Male Mutation Prostatic Neoplasms / metabolism* Prostatic Neoplasms / pathology Protein Conformation Protein Multimerization* Protein Transport Receptors, Androgen / chemistry* Receptors, Androgen / genetics Receptors, Androgen / metabolism* Signal Transduction Tumor Cells, Cultured
IF 3.998
DNA material pEGFP-hAR (RDB18673) pECFP-hAR (RDB18674) pEYFP-hAR (RDB18675) pcDNA3.1-FLAG-hAR (RDB18676) pGL3-phPSA -430 to +12 (RDB18677) 3xGRE-TK-pGL3 (RDB18678) GR-pCR3.1 (RDB18679) pEGFP-GR (RDB18680) pECFP-GR (RDB18681)