Structural basis for binding multiple ligands by the common cytokine receptor gamma-chain

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• The common gamma-chain (gamma(c)) is a critical component of receptors for multiple interleukins (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21).
• Understanding the structural basis of gamma(c) interaction with these diverse cytokines is essential for comprehending immune signaling pathways.

Purpose of the Study:

• To define the structural contributions of the gamma(c) ectodomain to the binding of six distinct cytokines.
• To identify specific residues on gamma(c) involved in mediating interactions with various interleukins.

Main Methods:

• Epitope mapping using antagonistic anti-gamma(c) monoclonal antibodies.
• Identification of critical amino acid residues (Asn-128, Tyr-103, Cys-161, Cys-210, Cys-211) involved in cytokine binding.

Main Results:

• Asn-128 was identified as a contact residue for IL-2, IL-7, and IL-15 binding, but not IL-4.
• Tyr-103, Cys-161, Cys-210, and Cys-211 were implicated in binding IL-4 and IL-15, in addition to IL-2 and IL-7.
• Data support a model of largely overlapping, yet distinct, binding sites on gamma(c) for multiple cytokines.

Conclusions:

• Gamma(c) utilizes a conserved mechanism for interacting with diverse cytokines.
• Specific residues like Asn-128 and Tyr-103 act as direct contact points, while cysteines may stabilize the interaction surface.
• These findings provide a refined structural model for gamma(c)-cytokine interactions.