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Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
The transmembrane glycoprotein gp130 is the common signal
transducing receptor subunit of the IL-6-type cytokines. The gp130
extracellular part is predicted to consist of six individual domains.
Whereas the role of the three membrane-distal domains (D1–D3) in
binding of IL-6 and IL-11 is well established, the function of the
membrane-proximal domains (D4–D6) is unclear. Mapping of a
neutralizing mAb to the membrane-proximal part of gp130 suggests a
functional role of D4–D6 in receptor activation. Individual deletion
of these three domains differentially interferes with ligand binding of
the soluble and membrane-bound receptors. All deletion mutants do not
signal in response to IL-6 and IL-11. The deletion mutants 
4 and, to
a lesser extent, 6 are still activated by agonistic monoclonal gp130
Abs, whereas the deletion mutant 5 does not respond. Because
membrane-bound 5 binds IL-6/soluble IL-6R as does wild-type gp130,
but does not transduce a signal in response to various stimuli, this
domain plays a prominent role in coupling of ligand binding and signal
transduction. Replacement of the fifth domain of gp130 by the
corresponding domain of the homologous G-CSF receptor leads to
constitutive activation of the chimera upon overexpression in COS-7
cells. In HepG2 cells this mutant responds to IL-6 comparable to
wild-type gp130. Our findings suggest a functional role of the
membrane-proximal domains of gp130 in receptor activation. Thus, within
the hematopoietic receptor family the mechanism of receptor activation
critically depends on the architecture of the receptor
ectodomain.
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