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Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation.
Author(s) -
Kruse N.,
Shen B.J.,
Arnold S.,
Tony H.P.,
Müller T.,
Sebald W.
Publication year - 1993
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1993.tb06207.x
Subject(s) - biology , environmental ethics , philosophy
Interleukin 4 (IL‐4) exerts a decisive role in the coordination of protective immune responses against parasites, particularly helminths. A disregulation of IL‐4 function is possibly involved in the genesis of allergic disease states. The search for important amino acid residues in human IL‐4 by mutational analysis of charged invariant amino acid positions identified two distinct functional sites in the 4‐helix‐bundle protein. Site 1 was marked by amino acid substitutions of the glutamic acid at position 9 in helix A and arginine at position 88 in helix C. Exchanges at both positions led to IL‐4 variants deficient in binding to the extracellular domain of the IL‐4 receptor (IL‐4R(ex)). In parallel, up to 1000‐fold increased concentrations of this type of variant were required to induce T‐cell proliferation and B‐cell CD23 expression. Site 2 was marked by amino acid exchanges in helix D at positions 121, 124 and 125 (arginine, tyrosine and serine respectively in the wild‐type). IL‐4 variants affected at site 2 exhibited partial agonist activity during T‐cell proliferation; however, they still bound with high affinity to IL‐4R(ex). [The generation of an IL‐4 antagonist by replacing tyrosine 124 with aspartic acid has been described before by Kruse et al. (1992) (EMBO J., 11, 3237‐3244)]. These findings indicate that IL‐4 functions by binding IL‐4R(ex) via site 1 which is constituted by residues on helices A and C.(ABSTRACT TRUNCATED AT 250 WORDS)