Structural insights into gene repression by the orphan nuclear receptor SHP

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Small heterodimer partner (SHP) is an orphan nuclear receptor that acts as a transcriptional repressor.
• SHP plays a critical role in regulating bile acid and cholesterol homeostasis.
• E1A-like inhibitor of differentiation (EID1) is a known SHP-interacting protein implicated in SHP-mediated transcriptional repression.

Purpose of the Study:

• To elucidate the structural basis of the interaction between SHP and EID1.
• To understand the mechanism of SHP-mediated transcriptional repression.
• To identify key residues and interfaces involved in SHP-EID1 complex formation.

Main Methods:

• X-ray crystallography to determine the structure of the SHP-EID1 complex.
• Site-directed mutagenesis to investigate the functional significance of the SHP-EID1 interface.
• Biochemical assays to assess SHP repressor activity.

Main Results:

• The crystal structure revealed an unexpected EID1-binding site on the N terminus of SHP, distinct from the classical C-terminal cofactor-binding site.
• EID1 was found to mimic helix H1 of the nuclear receptor ligand-binding domain at the SHP-binding interface.
• Mutations in conserved residues at the SHP-EID1 interface disrupted protein interactions and impaired SHP repressor activity.

Conclusions:

• The study provides crucial structural insights into SHP cofactor recruitment and its repressor function.
• A conserved protein interface mediating SHP-EID1 interaction was identified, with potential implications for other orphan nuclear receptors.
• This finding advances the understanding of transcriptional repression mechanisms regulated by orphan nuclear receptors.