Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling

Area of Science:

• Structural biology
• Immunology
• Molecular signaling

Background:

• The role of structural dynamics in type I interferon (IFN) receptor signaling remains unclear.
• Understanding IFNAR1 dynamics is crucial for deciphering its regulatory mechanisms in immune responses.

Purpose of the Study:

• To investigate the dynamics of the type I interferon receptor (IFNAR1) and its impact on signaling.
• To elucidate how IFNAR1 flexibility influences ligand binding and downstream biological effects.

Main Methods:

• Structure-based mechanistic studies
• In situ binding assays
• Gene induction assays
• Computational prediction and experimental validation of disulfide bonds to modulate receptor dynamics

Main Results:

• IFNAR1 flexibility modulates ligand-binding affinity, thereby regulating biological signaling.
• Key hinge sites and inter-subdomain movements (SD1-SD4) critical for accommodating intermolecular interactions were identified.
• Engineered disulfide bonds confirmed to interfere with IFNAR1 dynamics.
• Modulating SD2-SD3 flexibility altered IFN binding and activity, with decreased cooperative movement attenuating activity.
• Locking SD3-SD4 interface flexibility favored an extended conformer and increased activity.

Conclusions:

• IFNAR1 structural dynamics are a key determinant of its signaling capacity.
• Targeting IFNAR1 flexibility offers a potential strategy for modulating type I interferon responses.