Molecular models of two competitive inhibitors, IL-2 δ2 and IL-2 δ3, generated by alternative splicing of human interleukin-2

Abstract

Molecular models of IL-2 δ2 and IL-2 δ3, two alternative splice variants of human IL-2 without exon 2 and 3, respectively, are described. These alternative splice variants attract particular interest as potential competitive inhibitors of the cytokine. Tertiary structure of IL-2 consists of four-helix bundle including helices A, B, C and D and a β-pleated sheet. Exon 2 encodes the A–B loop (Asn30–Lys49 residues) linking helices A and B running in one direction. Rotation of the helix A around putative centre during the construction of IL-2 δ2 model have not produced any significant changes in the hydrophobic core of IL-2 molecule. However, a large hole was formed on the surface of IL-2 δ2 molecule instead of A–B loop in IL-2 fold. A high affinity IL-2 receptor is formed by combination of α, β, and γ c chains. Comparison of the model of the receptor bound IL-2 with the model of IL-2 δ2 has shown that their β-chain binding sites have minimum differences as distinct from α and γ c chain-binding sites. Exon 3 encodes Ala50–Lys97 fragment which forms helices B and C with their short connecting loop. Model IL-2 δ3 consists of helices A and D and long linking loop. This loop was composed of A–B and C–D loops which run in opposite directions in IL-2 structure and contain β-strands making a β-pleated sheet. Conformation of the linking loop relatively to helices A and D was stabilized by creation of a disulphide bond between cysteines 105 and 125. In addition, the hydrophobic residues of β-sheet interact with the hydrophobic surface of A–D helical complex and close the latter from contacts with solution. Comparison of the model of IL-2 bound to receptor with IL-2 δ3 model has shown that absence of helices B and C in IL-2 δ3 model results in insignificant conformational changes only in residues interacting with γ c chain of the receptor. The β/ γ c heterodimer is an intermediate affinity receptor of IL-2. Most likely, both IL-2 δ2 and IL-2 δ3 are naturally occurring IL-2 antagonists since they keep the ability of binding with an intermediate affinity receptor of this cytokine and fail to engage the α chain of its high affinity receptor.