Structure and specificity of nuclear receptor–coactivator interactions
- Beatrice D. Darimont1,2,
- Richard L. Wagner2,3,
- James W. Apriletti4,
- Michael R. Stallcup5,
- Peter J. Kushner4,
- John D. Baxter4,
- Robert J. Fletterick6, and
- Keith R. Yamamoto1,7
- 1Department of Cellular and Molecular Pharmacology, 3Graduate Group in Biophysics, 6Department of Biochemistry and Biophysics, 4Metabolic Research Unit, University of California at San Francisco (UCSF), San Francisco, California 94143 USA; 5Department of Pathology, University of Southern California, Los Angeles, California 90033 USA
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.
