Non-core region modulates interleukin-11 signaling activity: generation of agonist and antagonist variants.
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.
From the Department of Medical Genome Science, School of Frontier Sciences, and.
Saeko
S
Yanaka
From the Department of Medical Genome Science, School of Frontier Sciences, and.
中冴子
中
谷
From the Department of Medical Genome Science, School of Frontier Sciences, and; The Institute of Medical Science, The University of Tokyo, Kashiwa 277-8562 and.
Emiko
E
Sano
From the Department of Medical Genome Science, School of Frontier Sciences, and; The Institute of Medical Science, The University of Tokyo, Kashiwa 277-8562 and.
野恵海子
野
佐
Proteios Inc., Kamakura, 248-8555, Japan.
Norio
N
Naruse
Proteios Inc., Kamakura, 248-8555, Japan.
瀬紀男
瀬
成
From the Department of Medical Genome Science, School of Frontier Sciences, and.
Kin-Ichiro
KI
Miura
From the Department of Medical Genome Science, School of Frontier Sciences, and.
浦謹一郎
浦
三
From the Department of Medical Genome Science, School of Frontier Sciences, and.
Mutsumi
M
Futatsumori-Sugai
From the Department of Medical Genome Science, School of Frontier Sciences, and.
ツ森ー菅井睦美
ツ
二
From the Department of Medical Genome Science, School of Frontier Sciences, and; The Institute of Medical Science, The University of Tokyo, Kashiwa 277-8562 and.
Jose M M
JMM
Caaveiro
From the Department of Medical Genome Science, School of Frontier Sciences, and; The Institute of Medical Science, The University of Tokyo, Kashiwa 277-8562 and. Electronic address: tsumoto@k.u-tokyo.ac.jp.
Kouhei
K
Tsumoto
From the Department of Medical Genome Science, School of Frontier Sciences, and; The Institute of Medical Science, The University of Tokyo, Kashiwa 277-8562 and.
本浩平
本
津
D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D017370:Interleukin-11 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046188:Protein Modification, Translational / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship
C508611:IL11 protein, human; C494199:IL6ST protein, human; D017370:Interleukin-11; D050822:Cytokine Receptor gp130