MED1 Coactivation of Androgen Receptor‐dependent Transcription is Mediated Through a Newly Discovered Noncanonical Binding Motif

Abstract

The androgen receptor (AR) is uncommon among Nuclear receptor (NR) because of its intramolecular interaction(termed the N/C interaction) and thus coactivators can alternatively bind to surfaces in the AR amino terminal. The Mediator complex plays a key coregulatory role in steroid hormone dependent transcription and is chiefly targeted to NRs via the LxxLL‐containing MED1 subunit. However, the mechanisms by which AR recruits MED1 have remained unclear. Here we show that MED1 binds to a distinct AR amino‐terminal region termed transactivation unit‐1 (Tau‐1) via two newly discovered noncanonical α‐helical motifs of MED1. The two MED1 LxxLL motifs are not required for AR binding whereas loss of the intramolecular AR N/C interaction decreases MED1 binding. We further demonstrate that mitogen‐activated protein kinase phosphorylation of MED1 enhances the AR‐MED1 interaction in prostate cancer cells. In sum, our findings reveal a novel AR‐coactivator binding mechanism that may have clinical implications for AR activity in prostate cancer.