Jp. Thompson et W. Debinski, Mutants of interleukin 13 with altered reactivity toward interleukin 13 receptors, J BIOL CHEM, 274(42), 1999, pp. 29944-29950
Interleukin 13 (IL13) belongs to a family of cytokines whose members exhibi
t structural homology, despite amino acid sequence dissimilarity. For examp
le, while of limited sequence homology, IL13 and IL4 share a signaling rece
ptor, IL13/4 receptor, on a variety of human normal cells. However, a subcl
ass of II4-independent IL13 receptors is overexpressed on certain transform
ed cells, including human malignant gliomas. We introduced mutations into h
uman (h) IL13 to determine the site(s) involved in interaction with the sha
red receptor and/or the glioma-associated receptor. This analysis identifie
d at least three protein regions that are needed for signaling through the
shared receptor. These regions were localized to alpha-helices A, C, and D
and were mainly separate from the region(s) needed to interact with the gli
oma-associated receptor. Glutamic acids at positions 13 and 16 in hIL13 alp
ha-helix A, arginine and serine at positions 66 and 69 in helix C, and argi
nine at position 109 in helix D were found to be important in inducing biol
ogical signaling since their specific mutation resulted in loss and/or gain
of function phenomena. We demonstrate that the molecular requirements of h
IL13 to interact with its respective receptors are generally distinct and c
an be controlled by mutagenesis of the cytokine.