Non-core region modulates interleukin-11 signaling activity: Generation of agonist and antagonist variants

Saeko Yanaka, Emiko Sano, Norio Naruse, Kin Ichiro Miura, Mutsumi Futatsumori-Sugai, Jose M.M. Caaveiro, Kouhei Tsumoto

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8085-8093
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number10
DOIs
Publication statusPublished - Mar 11 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Non-core region modulates interleukin-11 signaling activity: Generation of agonist and antagonist variants'. Together they form a unique fingerprint.

Cite this