Hexameric Structure and Assembly of the Interleukin-6/IL-6 α-Receptor/gp130 Complex

Boulanger, Martin J.; Chow, Dar‐Chone; Brevnova, Elena E.; García, K. Christopher

doi:10.1126/science.1083901

Cited by 560 publications

(674 citation statements)

References 21 publications

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“…Because two Args (Arg-166 and -169 in hGCSF) in ␣D are conserved between hGCSF and hIL-6, and the model of the 2:2:2 (hGCSF͞hGCSF-R͞hIL-6R␣) complex can be built without any steric hindrance, the hIL-6R␣ binding to GCSF͞ hIg-CRH was tested by using surface plasmon resonance. It was found that hIL-6R␣ exhibited moderate affinity (K D ϭ 1.02 ϫ 10 Ϫ7 M) for hGCSF͞hIg-CRH complex that is comparable with the affinity between hIL-6 and hIL-6R␣ (13). Although the Ala mutations of Arg-166 and -169 in hGCSF did not show any effect on proliferation activity (17), the structural information for hGCSF͞hGCSF-R might suggest other functions of IL-6␣ in the signaling pathway of GCSF-R.…”

Section: Discussionmentioning

confidence: 79%

“…The signaling 2:2 complex is formed by means of cross-over interactions between the Ig-like domain of hGCSF-R and the neighboring hGCSF, forming a twofold axis of crystallographic symmetry. This conformation is quite different from that of the heterogeneous mouse GCSF-R complex and more closely resembles the 2:2:2 active assembly of human interleukin-6 (hIL-6), hIL-6 ␣-receptor (hIL-6R␣), and human gp130 [which is a shared signal transducing receptor for several cytokines (13)], and the 2:2 assembly of viral IL-6 (vIL-6) and human gp130 (14).…”

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confidence: 99%

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Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex

Tamada

Honjo²,

Maeda³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

114

117

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A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (GCSF) and a ligand binding region of GCSF receptor (GCSF-R), has been determined to 2.8 Å resolution. The GCSF:GCSF-R complex formed a 2:2 stoichiometry by means of a cross-over interaction between the Ig-like domains of GCSF-R and GCSF. The conformation of the complex is quite different from that between human GCSF and the cytokine receptor homologous domain of mouse GCSF-R, but similar to that of the IL-6͞gp130 signaling complex. The Ig-like domain cross-over structure necessary for GCSF-R activation is consistent with previously reported thermodynamic and mutational analyses.ligand-receptor interaction ͉ x-ray crystallography ͉ IL-6 ͉ gp130

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex

Tamada

Honjo²,

Maeda³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

114

117

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“…Then, the CBD of some large-size cytokine receptors (gp130, IL-12R␤1, and granulocyte-colony stimulating factor) interact with the cytokine(s) through site II (57,(61)(62)(63)(64). Recruitment of an additional site of interaction (site III) located on the Ig-like domain of a second large-size receptor leads to oligomerization and signaling of the receptor complex (65)(66)(67)(68)(69). Because no Ig-like domain is present in GPL, we can hypothesize that GPL should interact with its potential ligand(s) through a site II or a site I. GPL also likely implicates a neighbor receptor holding an Ig-like module to define the site III and to allow the dimerization process of large-size signaling subunits and subsequent signaling events.…”

Section: Discussionmentioning

confidence: 99%

GPL, a Novel Cytokine Receptor Related to GP130 and Leukemia Inhibitory Factor Receptor

Diveu

Lelièvre

Perret

et al. 2003

Journal of Biological Chemistry

104

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We describe a novel cytokine receptor named GP130 Like receptor, or GPL, that displays similarities with the interleukin-6 and interleukin-12 family of signaling receptors. Four different isoforms diverging in their carboxyl terminus were isolated, corresponding to proteins encompassing 560, 610, 626, and 745 amino acids. Sequences included a signal peptide of 32 amino acids, followed by a cytokine binding domain containing four conserved cysteines, a WSDWS motif, and a region consisting of three fibronectin type III domain repeats. No immunoglobulin-like module was identified in the GPL sequences. The intracellular part of longer isoforms contained a proline-rich region defining a box1 motif for interaction with the Janus kinases. The Gpl gene is organized in 15 exons and is located on 5q11.2 in tandem with the gp130 gene. Both genes were only separated by 24 kilobases, with opposite transcriptional orientations. The GPL receptor displayed a 28% identity with gp130. Specific GPL transcripts were observed in tissues involved in reproduction. Transcripts were also found in blood cells and in bone marrow, revealing expression of GPL in all of the myelomonocytic lineage, from hematopoietic stem cells to activated dendritic cells. In monocytes and dendritic cells, expression of GPL was strongly up-regulated by interferon-␥, indicating a possible involvement of GPL in Th1-type immune responses. The molecular basis of cell signaling mediated by GPL was studied using chimeric receptors where external portions of ␣ or ␤ interleukin-5 receptor subunits were fused to the internal portion of GPL or of related receptors. Results indicated that association of GPL to the intracellular portions of gp130, or LIF receptor, allowed the signaling cascade.

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“…The IL-6 receptor system consists of two functional molecules, an 80-kDa ligand-binding chain (IL-6R) and a 130-kDa nonligand-binding but signal-transducing chain (gp130). The anti-IL-6R Ab blocks the binding of IL-6 to the IL-6R (38,39). The anti-IL-6R Ab or the control Ab was i.p.…”

Section: Elimination Of Il-6 Signaling Reduces Liver Toxicitymentioning

confidence: 99%

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Koizumi

Yamaguchi

Kono

et al. 2007

The Journal of Immunology

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Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c+ cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.

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Hexameric Structure and Assembly of the Interleukin-6/IL-6 α-Receptor/gp130 Complex

Cited by 560 publications

References 21 publications

Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex

Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex

GPL, a Novel Cytokine Receptor Related to GP130 and Leukemia Inhibitory Factor Receptor

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

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