The Dynamics of Signal Triggering in a gp130-Receptor Complex

Matadeen, Rishi; Hon, Wai-Ching; Heath, John K.; Jones, E Y; Fuller, Stephen D.

doi:10.1016/j.str.2007.02.006

Cited by 70 publications

(62 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3, with contacts mediated by residues within domain 1 of gp130 and present in the flexible loop between helices S2 and D of IL-6 and in helix S1 (6). Interestingly, the surface of gp130 domain D1 involved in binding to IL-6/IL-6R␣ is shared by IL-11, which appears to form a similar hexameric signaling complex (29,30). This site is also used by a functional homolog of hIL-6 from Kaposi sarcoma-associated herpesvirus (viral IL-6), which in contrast to IL-6 has no requirement to interact with IL-6R␣ and signals via formation of a tetrameric viral IL-6/gp130 complex (31,32).…”

Section: Discussionmentioning

confidence: 99%

Conservation of Functional Sites on Interleukin-6 and Implications for Evolution of Signaling Complex Assembly and Therapeutic Intervention

Veverka

Baker

Redpath

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Interleukin-6 signaling requires assembly of a ternary IL-6/IL-6R␣/gp130 complex. Results: Determination of the mIL-6 structure allowed detailed structural and sequence comparisons with hIL-6, predicting the primacy of sites in driving IL-6/IL-6R␣-gp130 interactions, which was confirmed by binding experiments. Conclusion:Interactions between gp130 domain-1 and IL-6/IL-6R␣ drive signaling complex assembly. Significance: This suggests a pathway for evolution of signaling complex assembly and strategies for therapeutic targeting.

show abstract

Section: Discussionmentioning

confidence: 99%

Conservation of Functional Sites on Interleukin-6 and Implications for Evolution of Signaling Complex Assembly and Therapeutic Intervention

Veverka

Baker

Redpath

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Most of these ligand-occupied receptor complexes consist of a a-receptors (IL6Ra, IL11Ra, CNTFRa, and CT1Ra) and signal-transducing b-receptors (GP130, LIFR, OSMR, IL27R/WSX-1, and IL31R/GPL), although LIF, OsM, and IL31 appear to from complexes comprising b-chains only (9). Binding of IL11 or IL6 to their respective ligandspecific a-receptors subunits results in sequential assembly with GP130 to form trimers with a geometry facilitating a cooperative transition into high-affinity, signaling-competent hexameric complexes comprising a 2:2:2 ratio of ligand, a-receptor and GP130 (13).…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers

Ernst

Putoczki

2014

Clinical Cancer Research

View full text Add to dashboard Cite

Emerging evidence suggests that cytokines produced by inflammatory cells act as rheostats to link the degree of wounding and local inflammation to epithelial cell survival, proliferation, and metabolism that collectively underpin the repair response. Among these cytokines, the GP130 family, which encompasses, among others, IL6 and IL11, plays a major role in orchestrating these complex processes through the activation of the latent signal transducer and activator of transcription 3 (STAT3) in the epithelium. However, many of the molecular mechanisms that govern and ensure effective epithelial wound healing and regeneration renewal also promote tumorigenesis and the progression of established cancers. Accordingly, GP130 cytokines endow the inflammatory tumor microenvironment with a capacity to promote "cancer hallmark capabilities" of the malignant epithelium, while simultaneously suppressing the antitumor response of innate and adaptive immune cells. Here, we review some recent insights derived from genetic and therapeutic inhibition of the IL6/IL11-GP130-STAT3 signaling cascade in the context of preclinical mouse models of cancer, which are likely to have implications to other solid malignancies. Clin Cancer Res; 20(22); 5579-88. Ó2014 AACR.

show abstract

“…Low resolution electron microscopy (EM) images showed that the legs approach each other close to the membrane in a number of signaling-competent gp130 complexes (5,13,14). It has also been established by mutagenesis that the legs of the receptor provide an essential geometry required for signaling (15)(16)(17).…”

mentioning

confidence: 99%

Crystal Structure of the Entire Ectodomain of gp130

Kershaw

Luo

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

gp130 is the shared signal-transducing receptor subunit for the large and important family of interleukin 6-like cytokines. Previous x-ray structures of ligand-receptor complexes of this family lack the three membrane-proximal domains that are essential for signal transduction. Here we report the crystal structure of the entire extracellular portion of human gp130 (domains 1-6, D1-D6) at 3.6 Å resolution, in an unliganded form, as well as a higher resolution structure of the membraneproximal fibronectin type III domains (D4 -D6) at 1.9 Å . This represents the first atomic resolution structure of the complete ectodomain of any "tall" cytokine receptor. These structures show that other than a reorientation of the D1 domain, there is little structural change in gp130 upon ligand binding. They also reveal that the interface between the D4 and D5 domains forms an acute bend in the gp130 structure. Key residues at this interface are highly conserved across the entire tall receptor family, suggesting that this acute bend may be a common feature of these receptors. Importantly, this geometry positions the C termini of the membrane-proximal fibronectin type III domains of the tall cytokine receptors in close proximity within the transmembrane complex, favorable for receptor-associated Janus kinases to trans-phosphorylate and activate each other.

show abstract

The Dynamics of Signal Triggering in a gp130-Receptor Complex

Cited by 70 publications

References 41 publications

Conservation of Functional Sites on Interleukin-6 and Implications for Evolution of Signaling Complex Assembly and Therapeutic Intervention

Conservation of Functional Sites on Interleukin-6 and Implications for Evolution of Signaling Complex Assembly and Therapeutic Intervention

Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers

Crystal Structure of the Entire Ectodomain of gp130

Contact Info

Product

Resources

About