Identification of Single Amino Acid Residues of Human IL-6 Involved in Receptor Binding and Signal Initiation

Ehlers, Marc; Grötzinger, Joachim; Fischer, Martina; Bos, Hanny Klaasse; Brakenhoff, Just P. J.; Rose-John, Stefan

doi:10.1089/jir.1996.16.569

Cited by 27 publications

(20 citation statements)

References 41 publications

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“…This mutant is specific for IL-6 since it antagonizes the activity of IL-6, but not that of LIF, OSM, or GM-CSF on TF-I cells . A similar mutant, (Lys 54 Asp, Phe 170 Leu, Ser 176 Arg, Gln 159 Glu, Thr 162 Pro)ILd, was also shown to act as an IL-6 antagonist on XG-I cells (Ehlers et al, 1996). Ehlers et al (1995) narrowed down the region in helix A/ABloop by showing that substitution of residues Cys 50-Asp 55 for the corresponding mouse residues on a backbone of (Gln 159 Glu, Thr 162 Pro, Phe 170 Leu, Ser 176 Arg)ILd yielded similar antagonist activity.…”

Section: L-6 Residues Implicated In Il-6r-dependent Interaction Withmentioning

confidence: 93%

“…The substitution of a hydrophilic, charged residue for Leu 57 would cause greater disruption to any hydrophobic interactions involving Leu 57 (for example in the suggested interaction with the Dl motif) than the relatively conservative substitution to alanine, and could explain the greater loss of bioactivity of the latter mutant compared to (Leu 57 A1a)IL-6. Similarly, the substitution of Lys 54 for aspartic acid (Ehlers et al, 1996) but not for alanine (de Hon et al, 1995a) was found to negatively affect IL-6R-dependent gp130 binding of IL-6. By similarity to the AB-loop helix in G-CSF (Hill et al, 1993), it is likely that Lys 54 and Glu 5 1 participate in a stabilizing interaction on the putative AB-loop helix of IL-6.…”

Section: The High Affinity Ternary Il-6 Receptor-complex Is a Hexamermentioning

confidence: 93%

“…and the region encompassing Gly 77-Glu 95 (Ehlers et al, 1994) may form part of site I in IL-6. With the exception of Phe 78 (Ehlers et al, 1996). which is discussed in Determination of the active site, the individual residues in the latter region have not yet been identified and are therefore not marked.…”

Section: Il-6: Structure-function Relationshipsmentioning

confidence: 99%

“…In addition to both the Nand C-terminal regions of IL-6 being required for efficient binding to sIL-6R (Fiorillo et al, 1992a;van Dam et al, 1993;Hammacher et al, 1994), a region comprising part of the AB-loop through to the beginning of helix C (Leu 62-Arg 113) (Hammacher et al, 1994) and a region encompassing Lys 41-Glu 95 of IL-6 were identified as critical for the interaction with the IL-6R. Ehlers et al (1994) further narrowed down this region to residues Gly 77-Glu 95 in the AB-loop/helix B, and recently suggested that Phe 78 is involved in binding to the ILdR (Ehlers et al, 1996). Although the equivalent residue is not seen in the crystal structure of G-CSF (Hill et al, 1993), it is possible that Phe 78 stabilizes the orientation of the end of the AB-loop in IL-6, in a similar way to Leu 67 in CNTF .…”

Section: Il-6 Residues Implicated In Binding the Il-6r: Site Imentioning

confidence: 99%

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Interleukin‐6: Structure‐function relationships

et al. 1997

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Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-1 1, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affhity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.

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Section: L-6 Residues Implicated In Il-6r-dependent Interaction Withmentioning

confidence: 93%

Section: The High Affinity Ternary Il-6 Receptor-complex Is a Hexamermentioning

confidence: 93%

Section: Il-6: Structure-function Relationshipsmentioning

confidence: 99%

Section: Il-6 Residues Implicated In Binding the Il-6r: Site Imentioning

confidence: 99%

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Interleukin‐6: Structure‐function relationships

et al. 1997

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“…As shown in Fig. 1A, the interaction sites of IL-6 with the receptor subunits have been named site I (contact site to IL-6R), site II (contact site to gp130) (14), and site III (contact site to gp130) (11,15,34). A schematic representation of the IL-6 receptor antagonists (Fig.…”

Section: Resultsmentioning

confidence: 99%

A New Type of Cytokine Receptor Antagonist Directly Targeting gp130

Renné

Kallen

Mullberg

et al. 1998

Journal of Biological Chemistry

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The interleukin-6-type family of cytokines bind to receptor complexes that share gp130 as a common signaltransducing subunit. So far, receptor antagonists for interleukin-6-type cytokines have been constructed that still bind to the specific ligand binding subunit of the receptor complex, but have lost the ability to stimulate gp130. Such receptor antagonists compete for a specific receptor of a member of the cytokine family. Interleukin-6 only binds to gp130 when complexed with the interleukin-6 receptor that exists as a membrane bound and soluble molecule. Here we have constructed fusion proteins that consist of the soluble form of the human interleukin-6 receptor covalently linked to interleukin-6 receptor antagonists. These fusion proteins directly bind to gp130. Moreover, at concentrations of 10 -50 nM they completely neutralize not only the biological activity of interleukin-6 but also of other cytokines of the interleukin-6-type family that act via gp130 homodimers or gp130/LIF-R heterodimers. Therefore, these gp130 targeting cytokine antagonists might be useful therapeutic tools in disease states that are related to cytokines of the interleukin-6 family.

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The family of the IL-6-Type cytokines: Specificity and promiscuity of the receptor complexes

et al. 1997

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The cytokines IL-6, LIF, CNTF, OSM, IL-11, and CT-1 have been grouped into the family of IL-6-type cytokines, since they all require gp130 for signal transduction. Interestingly, gp130 binds directly to OSM, whereas complex formation with the other cytokines depends on additional receptor subunits. Only limited structural information on these cytokines and their receptors is available. X-ray structures have been solved for the cytokines LIF and CNTF, whose up-up-down-down four-helix bundle is common to all of these cytokines, and for the receptors of hGH and prolactin, which contain two domains with a fibronectin III-like fold. Since cocrystallization and x-ray analysis of the up to four different proteins forming the receptor complexes of the IL-6-type cytokines is unlikely to be achieved in the near future, model building based on the existing structural information is the only approach for the time being. Here we present model structures of the complexes of human and murine IL-6 with their receptors. Their validity can be deduced from the fact that published mutagenesis data and the different receptor specificity of human and murine IL-6 can be understood. It is now possible to predict the relative positions and contacts for all molecules in their respective complexes. Such information can be used for the rational design of cytokine and receptor antagonists, which may have a valuable therapeutic perspective.

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Identification of Single Amino Acid Residues of Human IL-6 Involved in Receptor Binding and Signal Initiation

Cited by 27 publications

References 41 publications

Interleukin‐6: Structure‐function relationships

Interleukin‐6: Structure‐function relationships

A New Type of Cytokine Receptor Antagonist Directly Targeting gp130

The family of the IL-6-Type cytokines: Specificity and promiscuity of the receptor complexes

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