Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor.

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Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA

Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor.

Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93. Epub 2006 Feb 13.

PubMed ID

16477002 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Aldesleukin	Cytokine receptor common subunit gamma	Protein	Humans	Yes	Agonist	Details
Aldesleukin	Interleukin-2 receptor subunit beta	Protein	Humans	Yes	Agonist Modulator	Details

Polypeptides

Name	UniProt ID
Interleukin-2 receptor subunit beta	P14784	Details
Interleukin-2 receptor subunit alpha	P01589	Details
Interleukin-2	P60568	Details
Cytokine receptor common subunit gamma	P31785	Details