Identification of residues in the putative 5th helical region of human interleukin‐6, important for activation of the IL‐6 signal transducer, gp130

Abstract

interaction (respectively termed a-and 13-sites) have been Abstract We have previously shown that L58 in the putative 5th helical region of human interleuidn-6 (IL-6) is important for identified and are dispersed throughout the putative tertiary activation of the IL-6 signal transducer gpl30 Ide Hon et al.structure (reviewed in [9]). The a-site is spatially separated (1995) FEBS Lett. 369, 187-1911. To further explore the from the I~-sites (l~l-~a), and is comprised of residues in the importance of individual residues in this region for gpl30A-and D-helix and in the loop between helices A and B. The activation we have now combined Ala substitutions of residues 131-site comprises residues Q153-H165 at the end of the C-D E52, $53, $54, K55, E56, L58 and E60 with other substitutions loop and top of helix D, the 132-site residues K42-A57 coverin IL-6, known to affect gpl30 activation (QI60E and T163P).ing the loop created by the first cysteine bridge and part of the The combination mutant protein with L58A completely lost the putative 5th helical region in the A-B loop, and the I~a-site capacity to induce the proliferation of XG-I myeloma cells, and residues Y32, G36, S119 and V122, located in the A-and Ccould effectively antagonize wild type IL-6 activity on these cells, helix [8,10]. The a-and 133-site of IL-6 correspond to binding Moreover, the data suggest that besides L58, $54 particularly, but also E52, $53, K55 and E56 contribute to gpl30 activation, sites 1 and 2 of human growth hormone respectively [10,11]. In the hexameric IL-6-receptor complex, regions 131 and 132 are

A role for IL-27p28 as an antagonist of gp130-mediated signaling

“…Differences between the association of IL-27p28 and IL-6 with gp130 are due to two amino acid differences in the AB loop between IL-27p28 and IL-6 that increase the hydrophobicity of IL-27p28, and thus its affinity for gp130. Interestingly, it has previously been shown that mutations in the AB loop of human IL-6 contribute to the ability of mutant forms of IL-6 to antagonize wild-type IL-6 activity42. Furthermore, modeling studies incorporating fluorescence-correlation spectroscopy have proposed that a gp130 homodimer first binds one IL-6–IL-6Rα complex, and engages a second IL-6–IL-6Rα complex at higher ligand concentrations43.…”

Interleukin-6 N-Terminal Peptides Modulate the Expression of junB Protooncogene and the Production of Fibrinogen in HepG2 Cells

“…Studies with chimeras and mutant proteins defined three receptor binding sites, where site I (or site α; Brakenhoff et al, 1995Brakenhoff et al, , 1996 binds the gp80 and site II and III (Savino et al, 1994;Panoessa et al, 1995;Sporeno et al, 1996) bind to a gp130 chain (reviewed in Simpson et al, 1997). Studies with chimeras and mutant proteins defined three receptor binding sites, where site I (or site α; Brakenhoff et al, 1995Brakenhoff et al, , 1996 binds the gp80 and site II and III (Savino et al, 1994;Panoessa et al, 1995;Sporeno et al, 1996) bind to a gp130 chain (reviewed in Simpson et al, 1997).…”