| RRC ID |
67358
|
| 著者 |
Shizu R, Yokobori K, Perera L, Pedersen L, Negishi M.
|
| タイトル |
Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus.
|
| ジャーナル |
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.
|
| 巻・号 |
9(1)
|
| ページ |
16734
|
| 公開日 |
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
|
| リソース情報 |
| 遺伝子材料 |
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) |
