Structural and Biophysical Studies of the Human IL-7/IL-7Rα Complex

McElroy, Craig A.; Dohm, Julie A.; Walsh, Scott T. R.

doi:10.1016/j.str.2008.10.019

Cited by 86 publications

(132 citation statements)

References 49 publications

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“…IL-7Rα-ECD, sIL7Rα, and TSLPR coupling and binding kinetics were measured using a CM5 sensor chip. The receptors were amine-coupled to the sensor chip using previously described methods (55). Experiments were performed in 10 mM Hepes (pH 7.4), 150 mM NaCl, 3 mM EDTA, and 0.005% Tween-20 at 25°C.…”

Section: Methodsmentioning

confidence: 99%

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Lundström

Highfill

Walsh

et al. 2013

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

127

153

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Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Rα competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7Rα also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7Rα and also demonstrate a potentiating effect of sIL7Rα on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7Rα levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.immunology | soluble receptors | tolerance

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Section: Methodsmentioning

confidence: 99%

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Lundström

Highfill

Walsh

et al. 2013

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

127

153

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“…Thus galectin-9 binding to branched N-glycan on Gcgr may slow mobility and thereby enhance interactions with other regulatory glycoproteins. It is also possible that branched N-glycans interact within the receptor fold to enhance dimerization and/or affinity for ligand (57).…”

Section: N-glycan Branching Pathway We Demonstrate That Mgat5mentioning

confidence: 99%

N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway

Johswich

Longuet

Pawling

et al. 2014

Journal of Biological Chemistry

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Background:The hexosamine biosynthesis pathway to UDP-GlcNAc has been implicated in glucose homeostasis. Results: UDP-GlcNAc and Golgi N-acetylglucosaminyltransferases modify the N-glycans on glucagon receptor, which increases sensitivity to glucagon in vivo. Conclusion: The hexosamine biosynthesis pathway contributes to glucose homeostasis, in part through N-glycan branching on glucagon receptor. Significance: Hepatic Mgat5 and the N-glycan branching pathway may be a therapeutic target for control of glycemia.

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“…This glycosylation is not required, however, for formation of the ligand-receptor complexes, as structures using receptors purified from Escherichia coli have been (20,22). Still, the binding affinity between IL-7 and IL-7R has been demonstrated to be increased when IL-7R is glycosylated (20).…”

Section: Il-21 Is a Class I Cytokine That Exerts Pleiotropic Effects mentioning

confidence: 99%

“…Receptors of the ␥C cytokines are known to be universally N-glycosylated (20). This glycosylation is not required, however, for formation of the ligand-receptor complexes, as structures using receptors purified from Escherichia coli have been solved (20,22).…”

mentioning

confidence: 99%

Crystal Structure of Interleukin-21 Receptor (IL-21R) Bound to IL-21 Reveals That Sugar Chain Interacting with WSXWS Motif Is Integral Part of IL-21R

Hamming

Kang

Svensson

et al. 2012

Journal of Biological Chemistry

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Background:The class I cytokine IL-21 exerts pleiotropic effects on innate and adaptive immunity. Results: We obtained the crystal structure of the partially glycosylated IL-21 receptor (IL-21R) bound to IL-21. Conclusion: A sugar chain is an integral part of IL-21R. Significance: This structure offers an insight into the putative role of the class I cytokine receptor signature motif. IL-21 is a class I cytokine that exerts pleiotropic effects on both innate and adaptive immune responses. It signals through a heterodimeric receptor complex consisting of the IL-21 receptor (IL-21R) and the common ␥-chain. A hallmark of the class I cytokine receptors is the class I cytokine receptor signature motif (WSXWS). The exact role of this motif has not been determined yet; however, it has been implicated in diverse functions, including ligand binding, receptor internalization, proper folding, and export, as well as signal transduction. Furthermore, the WXXW motif is known to be a consensus sequence for C-mannosylation. Here, we present the crystal structure of IL-21 bound to IL-21R and reveal that the WSXWS motif of IL-21R is C-mannosylated at the first tryptophan. We furthermore demonstrate that a sugar chain bridges the two fibronectin domains that constitute the extracellular domain of IL-21R and anchors at the WSXWS motif through an extensive hydrogen bonding network, including mannosylation. The glycan thus transforms the V-shaped receptor into an A-frame. This finding offers a novel structural explanation of the role of the class I cytokine signature motif.IL-21 is a class I cytokine with a four-helix bundle structure arranged in an up-up-down-down topology typical for the class I cytokines (1). It exerts pleiotropic effects on both innate and adaptive immune responses. IL-21 is secreted by activated CD4 ϩ T cells, in particular T H 17 and T follicular helper cells, as well as natural killer cells (2). Not only do both T H 17 and T follicular helper cells produce IL-21, but this cytokine also plays an important role in promoting the development of T H 17 and T follicular helper cells by a feed-forward mechanism (3-8). Furthermore, IL-21 cooperates with other cytokines to increase the cytotoxicity of CD8 ϩ T cells and promotes proliferation of CD8 ϩ cells in the presence of antigens (9). IL-21 also influences antibody production by B cells (10). Recent studies demonstrated that IL-21 produced by CD4 ϩ cells is critical for the ability of CD8 ϩ T cells to control viral infection (11-13). The ability of IL-21 to augment immunity has spurred substantial interest in the therapeutic use of IL-21, and it is currently being evaluated in a number of clinical trials against, for example, metastatic melanoma and renal cancer (14).IL-21 signals through a heterodimeric receptor complex consisting of the private chain IL-21 receptor (IL-21R) 2 and the common ␥-chain (␥C), the latter being shared by IL-2, IL-4, . Upon binding of IL-21 to the receptor complex and subsequent receptor activation, signaling occurs through the Jak-STAT ...

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Structural and Biophysical Studies of the Human IL-7/IL-7Rα Complex

Cited by 86 publications

References 49 publications

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway

Crystal Structure of Interleukin-21 Receptor (IL-21R) Bound to IL-21 Reveals That Sugar Chain Interacting with WSXWS Motif Is Integral Part of IL-21R

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