Structural analysis and modeling of a synthetic interleukin-2 mimetic and its interleukin-2Rbeta2 receptor.
Peptide p1-30, which is composed of the 30 amino-terminal residues (alpha-helix A) of human interleukin-2 (IL-2), binds as a tetramer to the dimeric IL-2Rbeta2 receptor, whereas the entire IL-2 recognizes the tricomponent receptor IL-2Ralphabetagamma. p1-30 is an IL-2 mimetic that activates CD8 low lymphocytes and natural killer cells, because these cells produce IL-2Rbeta constitutively. It also induces a strong lymphokine-activated killer cell response. A series of truncated peptides were analyzed by circular dichroism and analytical centrifugation to elucidate the role of p1-30 residues. We propose a model where residues 10-30 of the p1-30 peptide form an alpha-helix with eight hydrophobic side chains on the same surface buried in a hydrophobic core when four anti-parallel helices combine to form a bundle. IL-2Rbeta dimerization was further studied, and three-dimensional models of the free IL-2Rbeta2 receptor and the p1-304.IL-2Rbeta2 complex were built by comparative modeling based on the crystal structure of the erythropoietin receptor complex, because this belongs to the same hematopoietin family as IL-2. These models suggest that binding of the p1-30 tetramer rotates the COOH-terminal domains and brings both transmembrane regions 50 A closer together, driving the association of the two intracytoplasmic domains that would transduce the signal into the cytoplasm.
Rose
Thierry
T
Département de Biologie Structurale et Chimie, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
Moreau
Jean-Louis
JL
Eckenberg
Ralph
R
Thèze
Jacques
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D007376:Interleukin-2 / Q000138:chemical synthesis / Q000737:chemistry*; D053646:Interleukin-2 Receptor beta Subunit; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
C508020:IL2RB protein, human; C508022:Il2rb protein, mouse; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D011994:Recombinant Proteins