Non-core Region Modulates Interleukin-11 Signaling Activity

• Published in: The Journal of biological chemistry 2011-03, Vol.286 (10), p.8085-8093
• Main Authors: Yanaka, Saeko, 谷, 中冴子, Sano, Emiko, 佐, 野恵海子, Naruse, Norio, 成, 瀬紀男, Miura, Kin-ichiro, 三, 浦謹一郎, Futatsumori-Sugai, Mutsumi, 二, ツ森ー菅井睦美, Caaveiro, Jose M.M., Tsumoto, Kouhei, 津, 本浩平
• Format: Article
• Language: English
• Subjects: Agonist; Antagonist; Calorimetry; Glycosylation; Interleukin; Protein Stability; Surface Plasmon Resonance (SPR)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.152561

Human interleukin-11 (hIL-11) is a pleiotropic cytokine administered to patients with low platelet counts. From a structural point of view hIL-11 belongs to the long-helix cytokine superfamily, which is characterized by a conserved core motif consisting of four α-helices. We have investigated the region of hIL-11 that does not belong to the α-helical bundle motif, and that for the purpose of brevity we have termed “non-core region.” The primary sequence of the interleukin was altered at various locations within the non-core region by introducing glycosylation sites. Functional consequences of these modifications were examined in cell-based as well as biophysical assays. Overall, the data indicated that the non-core region modulates the function of hIL-11 in two ways. First, the majority of muteins displayed enhanced cell-stimulatory properties (superagonist behavior) in a glycosylation-dependent manner, suggesting that the non-core region is biologically designed to limit the full potential of hIL-11. Second, specific modification of a predicted mini α-helix led to cytokine inactivation, demonstrating that this putative structural element belongs to site III engaging a second copy of cell-receptor gp130. These findings have unveiled new and unexpected elements modulating the biological activity of hIL-11, which may be exploited to develop more versatile medications based on this important cytokine.