N/C Interactions in AR Transactivation

Sarah El Kharraz, Vanessa Dubois, Kaisa-Mari Launonen, Laura Helminen, Jorma J Palvimo, Claude Libert, Elien Smeets, Lisa Moris, Roy Eerlings, Dirk Vanderschueren, Christine Helsen, Frank Claessens
Endocrinology, Volume 163, Issue 9, September 2022, bqac104
https://doi.org/10.1210/endocr/bqac104

Abstract

The androgen receptor (AR) plays a central role in the development and maintenance of the male phenotype. The binding of androgens to the receptor induces interactions between the carboxyterminal ligand-binding domain and the highly conserved ²³FQNLF²⁷ motif in the aminoterminal domain. The role of these so-called N/C interactions in AR functioning is debated. In vitro assays show that mutating the AR in the ²³FQNLF²⁷ motif (called AR^NoC) attenuates the AR transactivation of reporter genes, has no effect on ligand binding, but does affect protein-protein interactions with several AR coregulators. To test the in vivo relevance of the N/C interaction, we analyzed the consequences of the genomic introduction of the AR^NoC mutation in mice. Surprisingly, the AR^NoC/Y mice show a normal male development, with unaffected male anogenital distance and normal accessory sex glands, male circulating androgen levels, body composition, and fertility. The responsiveness of androgen target genes in kidney, prostate, and testes was also unaffected. We thus conclude that the N/C interactions in the AR are not essential for the development of a male phenotype under normal physiological conditions.

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