Conformational transition of a polycationic hinge domain contributes to DNA binding

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Nuclear receptors (NRs) are crucial ligand-activated transcription factors.
• The structured DNA-binding domain (DBD) and ligand-binding domain (LBD) are well-studied, but the function of intrinsically disordered regions, like the hinge, is unclear.

Purpose of the Study:

• To investigate the role of the hinge region in thyroid hormone receptor alpha (TRα) function.
• To understand the conformational changes in TRα upon DNA binding.

Main Methods:

• Five-microsecond molecular dynamics simulations of TRα alone and bound to DNA.

Main Results:

• DNA binding induces a significant structural transition in the TRα hinge region from helical to unwound.
• Protein-DNA binding is multivalent, involving direct hinge-DNA minor groove interactions and canonical DBD-DNA major groove interactions.
• DNA binding causes a global "closed-to-open" conformational change in TRα, reducing DBD-LBD interactions.

Conclusions:

• The DNA-induced hinge transition may promote TRα activation.
• The hinge region directly influences DNA conformation, contributing to protein-DNA recognition.
• These findings offer insights into the mechanism of TRα DNA recognition and conformational dynamics.