Abstract
The functional receptor complex of ciliary neurotrophic factor (CNTF), a member of the gp130 family of cytokines, is composed of CNTF, the CNTF receptor alpha (CNTFR), gp130, and the leukemia inhibitory factor receptor (LIFR). However, the nature of the receptor-mediated interactions in this complex has not yet been resolved. To address this issue we have determined the solution structure of the C-terminal or BC domain of CNTFR and studied the interactions of CNTFR with LIFR and gp130. We reported previously that the membrane distal cytokine-binding domain (CBD1) of LIFR could interact in vitro with soluble CNTFR (sCNTFR) in the absence of CNTF. Here we show that the CBD of human gp130 can also bind in vitro to sCNTFR in the absence of CNTF. In addition, the gp130 CBD could compete with the LIFR CBD1 for the binding of sCNTFR. Substitution of residues in the gp130 CBD, the LIFR CBD1, and the CNTFR BC domain that are expected to be involved in receptor-receptor interactions significantly reduced their interactions. An NMR chemical shift perturbation study of the interaction between the BC domains of CNTFR and gp130 further mapped the interaction surface. These data suggest that both the gp130 CBD and the LIFR CBD1 interact with CNTFR in a similar way and provide insights into the nature of the CNTF receptor complex.
Highlights
Ciliary neurotrophic factor (CNTF) belongs to the gp130 family of cytokines
We recently reported that the leukemia inhibitory factor (LIF) receptor (LIFR) CBD1 could interact with soluble CNTF receptor α (CNTFR) in vitro in the absence of CNTF [26]
The final ensemble of the lowest 20 energy structures of the CNTFR BC domain is shown in Fig. 2A, while in Fig. 2B a ribbon diagram representation of the average structure, in the same orientation, shows the fibronectin type III domain-like topology of seven β-strands in two anti-parallel β-sheets formed by these domains
Summary
Ciliary neurotrophic factor (CNTF) belongs to the gp130 family of cytokines. This family includes leukemia inhibitory factor (LIF), interleukin (IL)-6, IL-11, oncostatin M (OSM), cardiotrophin-1 (CT-1) and the newly identified cardiotrophin-like cytokine (CLC) [1,2,3]. CNTF enhances the survival of neuronal cells [4], and has been investigated as a therapeutic agent for motor neuron disease [5]. To exert its biological functions, CNTF first binds its non-signaling, specific receptor, CNTFR, which has been shown to be required for motor neuron development [8]. Signaling through the JAK/STAT pathway follows the recruitment of gp130 and the LIF receptor (LIFR) [9, 10]
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