Interleukin-2–Interleukin-2 receptor alpha protein-protein interface (IL-2–IL-2Rα PPI)

The Interleukin-2–Interleukin-2 receptor alpha (IL-2–IL-2Rα) protein-protein interface is a critical regulatory site in the immune system, governing the transition of the IL-2 receptor from an intermediate-affinity dimer to a high-affinity heterotrimeric complex. IL-2Rα (also known as CD25) does not possess an intracellular signaling domain but functions to capture IL-2 and present it to the signaling subunits, IL-2Rβ and γc (UniProt P01589). This interaction is essential for the rapid proliferation and survival of activated T cells and the maintenance of regulatory T cells (Tregs), making it a focal point for modulating immune responses (Liao et al., 2013, Immunity). In clinical practice, this interface is targeted by monoclonal antibodies like Basiliximab and Daclizumab to prevent organ transplant rejection and treat autoimmune conditions by blocking IL-2-mediated T-cell activation (Waldmann, 2006, Nature Reviews Immunology). Furthermore, the development of small-molecule inhibitors targeting this specific protein-protein interface represents a significant challenge and opportunity in drug discovery, aiming to provide oral alternatives to biologics for treating inflammation and cancer (Arkin & Wells, 2004, Nature Reviews Drug Discovery). Disrupting this interface allows for the selective inhibition of high-affinity IL-2 signaling while potentially sparing intermediate-affinity signaling on natural killer cells, offering a nuanced approach to immunotherapy (Malek, 2008, Annual Review of Immunology).

Other names

IL-2/CD25 interfaceIL-2/IL-2RA interaction siteInterleukin-2/CD25 complexIL-2:IL-2Rα binding interface

Competitive antagonism of the IL-2 binding site on the alpha subunit (CD25), preventing the assembly of the high-affinity heterotrimeric IL-2 receptor complex (αβγ) and subsequent STAT5 signaling.