title: Molecular models of two competitive inhibitors, IL-2delta2 and IL-2delta3, generated by alternative splicing of human interleukin-2.
abstract: Molecular models of IL-2delta2 and IL-2delta3, 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 beta-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-2delta2 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-2delta2 molecule instead of A-B loop in IL-2 fold. A high affinity IL-2 receptor is formed by combination of alpha, beta, and gamma(c) chains. Comparison of the model of the receptor bound IL-2 with the model of IL-2delta2 has shown that their beta-chain binding sites have minimum differences as distinct from alpha and gamma(c) chain-binding sites. Exon 3 encodes Ala50-Lys97 fragment which forms helices B and C with their short connecting loop. Model IL-2delta3 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 beta-strands making a beta-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 beta-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-2delta3 model has shown that absence of helices B and C in IL-2delta3 model results in insignificant conformational changes only in residues interacting with gamma(c) chain of the receptor. The beta/gamma(c) heterodimer is an intermediate affinity receptor of IL-2. Most likely, both IL-2delta2 and IL-2delta3 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 alpha chain of its high affinity receptor.
authors.affiliation: Institute of Immunological Engineering, Chekhov District, Moscow, Russia. aleden@utu.fi
authors.forename: A I
authors.initials: AI
authors.lastname: Denesyuk
authors.forename: V P
authors.initials: VP
authors.lastname: Zav'yalov
authors.forename: K A
authors.initials: KA
authors.lastname: Denessiouk
authors.forename: T
authors.initials: T
authors.lastname: Korpela
mesh_terms: D017398:Alternative Splicing; D001667:Binding, Competitive; D016208:Databases, Factual; D005091:Exons; D006801:Humans; D007376:Interleukin-2 / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors
chemical_list: D007376:Interleukin-2; D015375:Receptors, Interleukin-2