Structure of the IL3 receptor

Molecular biology of the murine IL-3 receptor

Using an antibody (Aic2) that partially blocked IL-3 binding to murine cells, a cDNA termed AIC2A was cloned that encoded an 878 amino acid protein including a signal sequence. The mature protein is a glycoprotein of about 120 kDa. The AIC2A protein is a member of the type I cytokine receptor super-family that includes the (3 and 7 subunits of the IL-2 receptor, the receptors for IL-4 through IL-7, IL-9, GM-CSF, G-CSF, erythropoietin, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor. They have a common structural motif in their extracellular domains. This motif contains approximately 200 amino acids with fibronectin type III modules. Each module contains seven antiparallel 3 strands. There are four conserved cysteines in the N-terminal module and a unique tryptophan-serine-variable amino acid-tryptophan-serine (WSXWS) motif in the C-terminal module.

The AIC2A protein binds murine IL-3 with very low affinity (iid = 10-20 nM). These binding characteristics are consistent with the low-affinity binding site on murine cells. A second cDNA was subsequently cloned that conferred high-affinity IL-3 binding in cooperation with AIC2A. The cDNA was termed SUT-1 and coded for a protein of 396 amino acids that is also a member of the type I cytokine receptor superfamily. The mature protein is about 70 kDa and binds IL-3 with a Kit of 40 n.M. Coex-pression of SUT-1 and AIC2A reconstitutes a receptor that binds murine IL-3 with a Kd of 300 pM. Thus, SUT-1 is now referred to as the a or ligand-binding subunit, and AIC2A as the 3 subunit of the murine IL-3 receptor. Further expression cloning using the Aic2 antibody led to the molecular cloning of a second AIC2 cDNA termed AIC2B. This cDN'A encodes a protein of 896 amino acids with 91% homology to AIC2A, and its structure is basically the same as the IL-3 receptor 3 subunit; however, AIC2B binds neither IL-3 nor any other cytokine. Further studies have revealed that AIC2A is a subunit specific to the IL-3 receptor binding complex, and AIC2B is a 3 subunit shared with the GM-CSF reccptor (Figure 1).

Molecular biology of the human IL-3 receptor

Using the AIC2A cDNA as a probe, the human homolog of the murine IL-3 receptor 3 subunit was cloned. The cDNA was termed KH97 and its overall structure was remarkably similar to the AIC2A/ AIC2B proteins. It is about 56% homologous to the amino acid sequence of the murine A1C2 proteins. KH97 has two WSXWS motifs, but does not bind any IL-3 or other cytokines. Expression cloning using a cotransfection strategy with KH97 cDNA allowed the isolation of a cDNA that bound IL-3 with extremely low affinity. This cDNA, termed DUK-1, encodes a protein of 378 amino acids, and the extracellular domain contains a single WSXWS motif. The mature protein is about 70 kDa, and its structure is similar to the murine IL-3 receptor a subunit. The murine and human proteins however, show only about 70% homology at the amino acid level.

Transfection of COS-7 cells with the human IL-3 receptor a cDNA (DUK-1) yielded cells that bound IL-3 with very low affinity (Kd = 100 nM); however.

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