Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes

Authors

Xinzhe Yu
Ping Yi
Ross A Hamilton
Hong Shen
Muyuan Chen
Charles E Foulds
Michael A Mancini
Steven J Ludtke
Zhao Wang
Bert W O'Malley

Publication Date

9-3-2020

Journal

Molecular Cell

DOI

10.1016/j.molcel.2020.06.031

PMID

32668201

PMCID

PMC7483370

PubMedCentral® Posted Date

9-3-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Cryoelectron Microscopy, DNA, E1A-Associated p300 Protein, HEK293 Cells, Humans, Nuclear Receptor Coactivator 3, Nucleic Acid Conformation, Protein Conformation, Receptors, Androgen, Recombinant Proteins, Androgen receptor, coactivator, SRC-3, p300, complex, cryoEM, structure

Abstract

Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2 (AF-2) is a primary contributor to the nuclear receptor (NR) transcriptional activity. In contrast to other steroid receptors, such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations. Here, we present cryoelectron microscopy (cryo-EM) structures of DNA-bound full-length AR and its complex structure with key coactivators, SRC-3 and p300. AR dimerization follows a unique head-to-head and tail-to-tail manner. Unlike ERα, AR directly contacts a single SRC-3 and p300. The AR NTD is the primary site for coactivator recruitment. The structures provide a basis for understanding assembly of the AR:coactivator complex and its domain contributions for coactivator assembly and transcriptional regulation.

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