Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Retinoic acid receptor-related orphan receptor γ (RORγ) is a nuclear receptor crucial for metabolism, immunity, and cancer.
• RORγ's function relies on recruiting coregulatory proteins, but its full-length complex assembly is poorly understood.
• Current structural data primarily focuses on the RORγ ligand-binding domain and short coregulator peptides.

Purpose of the Study:

• To investigate the ligand-dependent assembly of full-length RORγ:coregulator complexes on DNA response elements.
• To elucidate the structural mechanisms governing RORγ target gene regulation.
• To explore how DNA binding influences RORγ conformation and coregulator interaction.

Main Methods:

• Structural proteomics
• Small-angle X-ray scattering (SAXS)
• Analysis of full-length RORγ:coregulator complexes

Main Results:

• RORγ elongates upon DNA recognition, limiting interdomain communication.
• The DNA-binding domain adopts a sequence-specific conformation.
• Coregulatory proteins may sense the ligand- and DNA-bound state of RORγ.

Conclusions:

• A model is proposed where DNA sequence influences ligand-dependent coregulator recruitment by RORγ.
• DNA-dependent conformational changes are critical for regulating full-length RORγ activity.
• Findings provide insights into orphan nuclear receptor gene regulation.