Abstract
Interleukin-11 (IL-11) is a member of the gp130 family of cytokines. These cytokines drive the assembly of multisubunit receptor complexes, all of which contain at least one molecule of the transmembrane signaling receptor gp130. A complex of IL-11 and the IL-11 receptor (IL-11R) has been shown to interact with gp130, with high affinity, and to induce gp130- dependent signaling. In this study, we have identified residues crucial for the binding of murine IL-11 (mIL-11) to both the IL-11R and gp130 by examining the activities of mIL-11 mutants in receptor binding and cell proliferation assays. The location of these residues, as predicted from structural studies and a model of IL-11, reveals that mIL-11 has three distinct receptor binding sites. These are structurally and functionally analogous to the previously defined receptor binding sites I, II, and III of interleukin-6 (IL-6). This supports the hypothesis that IL-11 signals via the formation of a hexameric receptor complex and indicates that site III is a generic feature of cytokines that signal via association with gp130.
Highlights
Interleukin-11 (IL-11)1 is a secreted polypeptide cytokine
IL-11 has been shown to function in a similar manner, and, as for IL-6, a ligand-specific IL-11 receptor (IL11R) [15, 16] functions to promote the formation of a high affinity complex between IL-11 and gp130 [17]
These sites, termed sites I and II, allow IL-6 to form a trimer with the IL-6 receptor (IL-6R) and gp130, just as human growth hormone (hGH) forms a trimer with two receptors
Summary
Interleukin-11 (IL-11) is a secreted polypeptide cytokine. It was identified originally from its ability to stimulate the proliferation of a murine plasmacytoma cell line T1165 [1], it has been shown that IL-11 is widely expressed and has biological effects on a diverse range of cell types, including hematopoietic cells, hepatocytes, adipocytes, neurones, and osteoblasts (for review, see Ref. 2). (IL-6), oncostatin M, leukemia inhibitory factor (LIF), cardiotrophin-1, ciliary neurotrophic factor (CNTF), and an IL-6like protein encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV-IL-6) All of these cytokines elicit either hetero- or homodimerization of gp130 which activates intracellular signal transduction pathways via protein kinases belonging to the Janus kinase, mitogen-activated protein kinase, and Src families [7,8,9,10,11]. In addition to sites I and II, a third topologically distinct site has been identified for IL-6 which allows it to bind to a second gp130 molecule [14, 29] This site (site III) contributes to stabilizing the hexameric receptor complex. In this study we identify residues critical for the binding of mIL-11 to the IL-11R and gp130, which provides evidence that IL-11 has three topologically distinct receptor binding sites structurally and functionally equivalent to sites I, II, and III of IL-6
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