Structure and specificity of nuclear receptor–coactivator interactions

TLDR

Transcriptional regulation relies on flexible yet precise assembly of multiprotein complexes, where amphipathic α‑helices bind hydrophobic grooves and adjacent residues modulate affinity, enabling receptor‑specific interactions. The study proposes that shared structural motifs provide flexibility in combinatorial regulation while interface side chains confer receptor specificity. Structural studies show that hormone binding creates a hydrophobic groove in the thyroid hormone receptor LBD that engages an LxxLL motif α‑helix of the coactivator GRIP1.

Abstract

Combinatorial regulation of transcription implies flexible yet precise assembly of multiprotein regulatory complexes in response to signals. Biochemical and crystallographic analyses revealed that hormone binding leads to the formation of a hydrophobic groove within the ligand binding domain (LBD) of the thyroid hormone receptor that interacts with an LxxLL motif-containing α-helix from GRIP1, a coactivator. Residues immediately adjacent to the motif modulate the affinity of the interaction; the motif and the adjacent sequences are employed to different extents in binding to different receptors. Such interactions of amphipathic α-helices with hydrophobic grooves define protein interfaces in other regulatory complexes as well. We suggest that these common structural elements impart flexibility to combinatorial regulation, whereas side chains at the interface impart specificity.