Hormone-Dependent Coactivator Binding to a Hydrophobic Cleft on Nuclear Receptors

TLDR

The AF‑2 domain of nuclear receptor ligand‑binding regions mediates hormone‑dependent coactivator binding. Scanning mutagenesis of the thyroid hormone receptor revealed that a hydrophobic cleft, formed by the C‑terminal α‑helix folding against three other helices, serves as the coactivator binding site. The residues that encircle this cleft suggest a conserved coactivator‑binding motif common to nuclear receptors.

Abstract

The ligand-binding domain of nuclear receptors contains a transcriptional activation function (AF-2) that mediates hormone-dependent binding of coactivator proteins. Scanning surface mutagenesis on the human thyroid hormone receptor was performed to define the site that binds the coactivators, glucocorticoid receptor–interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1). The residues involved encircle a small surface that contains a hydrophobic cleft. Ligand activation of transcription involves formation of this surface by folding the carboxyl-terminal α helix against a scaffold of three other helices. These features may represent general ones for nuclear receptors.