Title : Crystal
structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine
receptor
Abstract :
- IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha , IL-2R beta , and gamma(c)
- Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3 .0 A resolution
- The quaternary structure is consistent with a stepwise assembly from IL-2 / IL-2R alpha to IL-2 / IL-2R alpha / IL-2R beta to IL-2 / IL-2R alpha / IL-2R beta / gamma(c)
- The IL-2R alpha subunit forms the largest of the three IL-2 / IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface
- Surprisingly, IL-2R alpha makes no contacts with IL-2R beta or gamma(c) , and only minor changes are observed in the IL-2 structure in response to receptor binding
- These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction
- Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2R beta and gamma(c) subunits
- Helix A of IL-2 wedges tightly between IL-2R beta and gamma(c) to form a three-way junction that coalesces into a composite binding site for the final gamma(c) recruitment
- The IL-2 / gamma(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes