Identification of three distinct receptor binding sites of murine interleukin-11

Interleukin-11 (IL-11) is a member of the gp130 family of cytokines. These cytokines drive the assembly of multisubunit receptor complexes, all of whi ch contain at least one molecule of the transmembrane signaling receptor gp 130. A complex of IL-11 and the IL-11 receptor (IL-11R) has been shown to i nteract with gp130, with high affinity, and to induce gp130- dependent sign aling. In this study, we have identified residues crucial for the binding o f murine IL-11 (mIL-11) to both the IL-11R and gp130 by examining the activ ities 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 sit es. These are structurally and functionally analogous to the previously def ined receptor binding sites I, II, and III of interleukin-6 (IL-6). This su pports the hypothesis that IL-11 signals via the formation of a hexameric r eceptor complex and indicates that site III is a generic feature of cytokin es that signal via association with gp130.