IL-2 Induces Conformational Changes in Its Preassembled Receptor Core, Which Then Migrates in Lipid Raft and Binds to the Cytoskeleton Meshwork

Pillet, Anne-Hélène; Lavergne, Vincent; Pasquier, Virginie; Gesbert, Franck; Thèze, Jacques; Rose, Thierry

doi:10.1016/j.jmb.2010.08.056

Cited by 39 publications

(57 citation statements)

References 50 publications

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“…7, g-i. This mechanism has also been proposed for the IL-2R␤⅐␥c homologous system (22,24). We found that a few min after IL-7 was added, about 300 membrane microdomains were formed over the entire surface of the T-cell (Figs.…”

Section: Sted Microscopy Analysis Of Il-7-induced Membrane Microdomaimentioning

confidence: 75%

Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells

Tamarit

Bugault

Pillet

et al. 2013

Journal of Biological Chemistry

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Background: Interleukin-7 is the master regulator of T-cell proliferation. Results: IL-7 drives its receptor in a membrane microdomain that regulates phosphorylation of associated tyrosine kinases JAK1 and JAK3, anchors IL-7 receptor to cytoskeleton and regulates STAT5 phosphorylation and nuclear translocation. Conclusion: Membrane microdomains and cytoskeleton scaffold IL-7R-signalosomes and assist signaling protein transport. Significance: Transient membrane and cytoskeleton organization shapes IL-7-signaling mechanisms in CD4 T-cells.

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Section: Sted Microscopy Analysis Of Il-7-induced Membrane Microdomaimentioning

confidence: 75%

Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells

Tamarit

Bugault

Pillet

et al. 2013

Journal of Biological Chemistry

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“…A stronger binding affinity was also observed for the interaction of full-length IL-7Rα with γ c than IL-7Rα self-association on the cell surface of T cells (13). Likewise, a higher binding affinity was observed for the interaction of full-length IL-2Rβ with γ c than IL-2Rβ self-association on cells (14,27). Further structural studies of IL-7Rα and γ c will shed light on the individual contributions of the ECD and TMD to IL-7-independent association.…”

Section: Resultsmentioning

confidence: 91%

“…Finally, experiments performed on other homodimeric α/β-receptors in the γ c family have shown that the ECDs, and not the transmembrane or intracellular domains, are responsible for dimerization. For instance, removal of the IL-2Rβ and γ c ECDs from the fulllength receptors abrogates IL-2Rβ homodimerization and IL-2Rβ/γ c heterodimerization (14). Although not tested (13), a similar result would likely occur with IL-7Rα and γ c .…”

Section: Structural Comparison Of Unliganded and Liganded States Of Imentioning

confidence: 99%

“…Neither the preassembly of IL-7Rα homodimers nor IL-7Rα-γ c heterodimers induces signaling (12,13). Similarly, preformed receptor homoand heterodimers have been reported for IL-2Rβ (14), IL-4Rα (15), and IL-9Rα (16). The preassembly model of cytokine receptors, first reported for the homotypic erythropoietin receptor (EPOR) (17), represents a new cytokine receptor signaling paradigm (reviewed in ref.…”

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confidence: 99%

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Structural reorganization of the interleukin-7 signaling complex

McElroy

Holland²,

Zhao³

et al. 2012

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

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We report here an unliganded receptor structure in the common gamma-chain (γ c ) family of receptors and cytokines. The crystal structure of the unliganded form of the interleukin-7 alpha receptor (IL-7Rα) extracellular domain (ECD) at 2.15 Å resolution reveals a homodimer forming an "X" geometry looking down onto the cell surface with the C termini of the two chains separated by 110 Å and the dimer interface comprising residues critical for IL-7 binding. Further biophysical studies indicate a weak association of the IL-7Rα ECDs but a stronger association between the γ c /IL-7Rα ECDs, similar to previous studies of the full-length receptors on CD4 + T cells. Based on these and previous results, we propose a molecular mechanism detailing the progression from the inactive IL-7Rα homodimer and IL-7Rα-γ c heterodimer to the active IL-7-IL-7Rα-γ c ternary complex whereby the two receptors undergo at least a 90°rotation away from the cell surface, moving the C termini of IL-7Rα and γ c from a distance of 110 Å to less than 30 Å at the cell surface. This molecular mechanism can be used to explain recently discovered IL-7-and γ c -independent gain-of-function mutations in IL-7Rα from B-and Tcell acute lymphoblastic leukemia patients. The mechanism may also be applicable to other γ c receptors that form inactive homodimers and heterodimers independent of their cytokines.X-ray crystallography | biophysics | homodimerization | cancer mutations

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“…IL-2 and IL-15 share a common receptor core of intermediate affinity (K d of 900 and 150 pM, respectively), formed by the dimeric association of IL-2R␤ (CD122) and the common gamma chain ␥ c (CD132) [10,11]. IL-2R␤ can also form homodimers that bind IL-2 and IL-15 with intermediate affinity [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Interleukin (IL)-2 and IL-15 have different effects on human natural killer lymphocytes

Pillet¹,

Thèze²,

Rose³

2011

Human Immunology

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IL-2 Induces Conformational Changes in Its Preassembled Receptor Core, Which Then Migrates in Lipid Raft and Binds to the Cytoskeleton Meshwork

Cited by 39 publications

References 50 publications

Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells

Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells

Structural reorganization of the interleukin-7 signaling complex

Interleukin (IL)-2 and IL-15 have different effects on human natural killer lymphocytes

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