IL-2 Immunoregulatory Cytokine Quaternary Complex

Rodaba Rahim '22 and Ben Stillions '22

Contents:

I. Introduction

Interleukin-2 (IL-2) is an immunoregulatory cytokine that is involved in signalling in the immune system. IL-2 plays a major part in immunity and tolerance with its effects on T-cells and B-cells, which are both types of white blood cells. It activates the proliferation, differentiation and survival of T-cells and B-cells, which are involved in immune response. IL-2 interacts with immature T-cells as well to differentiate them into regulatory T-cells, which suppress cells that are primed to attack healthy cells in the body. It also differentiates immature T-cells into effector T-cells and memory T-cells, which help fight infection. IL-2 is active when found in a quaternary receptor signalling complex, consisting of alpha (Il-2a), beta (Il-2B) and gamma chain (yc) receptors

II. General Structure

The IL-2 quaternary complex consists of the IL-2 with alpha (Il-2Ra) , beta (Il-2RB) and gamma chain (yc) receptors. IL-2 is characterized as an alpha helix, with its receptors as beta sheets Individual subunits have generally low affinity towards IL-2, but the quaternary complex has a high affinity. Binary complexes between Individual subunits and IL-2 have relatively low affinities, but the combined subunits forming the quaternary complex has a high affinity.

III. IL-2 and IL-2Ra

IL-2Ra binds with IL-2 in both the quaternary complex and a binary complex. IL-2 binds IL-2Ra with low affinity, however their binding causes a conformational change that increases IL-2 affinity with IL-2RB, stabilizing the complex. Hydrophobic ridges of IL-2 insert into grooves between the IL-2Ra beta strands through residues Phe42 and Tyr45. . These areas of contact are also accompanied by hydrogen bonds and van der waals contacts.There are H-bond interactions between Arg38 in IL-2 and Asp 4-6 on IL-2Ra. Also, Glu61 and Glu62 in IL-2 form hydrogen bonds with Asp36 and Ser 39. Van der waals contacts also aid in stabilizing relationship including between Lys35 in IL-2 and Leu2 in the attached subunit alpha receptor.

IV. IL-2 and IL-2RB

The binary complex formed between IL-2 and IL-2RB has a weak affinity, however it is not due to a lack of interactions between proteins. There are 8 hydrogen bonds that help connect IL-2 and IL-2RB residues. Also, water molecules bridge interactions between the two proteins. The reason for the complex’s low affinity is unknown, but it is speculated that solvent exchange could disrupt the water bridges that are formed, lowering the amount of interactions.

V. IL-2 and Yc

Two weak interactions, IL-2 and IL-2RB, and IL-2 and Yc, combine to produce an intermediate affinity complex consisting of IL-2, IL-2RB, and Yc. Out of these two interactions, IL-2 with Yc is the smaller one with minor contact patches, along with a water molecule bridge connecting Pro207 and Ser211 of Yc with Gln126 of IL-2.

VI. IL-2RB and Yc

The interaction surface between IL-2RB and Yc is the larger of the IL-2/IL-2RB/Yc complex. The interactions are formed mainly between D2 of IL-2RB and Yc. 21 IL-2RB and 19 from Yc. The interaction surface consists of 17 hydrogen bonds in the shape of a ring surrounding a hydrophobic “stripe” in the center formed by Trp166 from IL-2RB and Tyr167 from Yc.


VII. References

Dinarello, Charles A. 2007. Historical insights into cytokines. European journal of immunology 37 Suppl 1(Suppl 1), S34–S45. doi:10.1002/eji.200737772

Rickert, Mathias, Xinquan Wang, Martin J. Boulanger, Natalia Goriatcheva, K. Christopher Garcia. 2005. The structure of interleukin-2 complexed with its alpha receptor. Science 308:1477-1480.

Wang, Xinquan, Mathias Rickert, and K. Christopher Garcia. 2005. Structure of the quaternary complex of interleukin-2 with its a, B, and Yc receptors. Science 310:1159-1163.

Stauber, Deborah J., Erik W. Debler, Patricia A. Horton, Kendall A. Smith, Ian A. Wilson. 2006. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proceedings of the National Academy of Sciences of the United States of America 103:2788–2793. doi:10.1073/pnas.0511161103

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