IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling

Goepfert, A.; Barske, Carmen; Lehmann, Sylvie; Wirth, Emmanuelle; Willemsen, Joschka; Guðjónsson, Jóhann E.; Ward, Nicole L.; Sarkar, Mrinal K.; Hemmig, R.; Frank, Konstantin; Rondeau, Jean‐Michel

doi:10.1016/j.celrep.2022.111489

Cited by 15 publications

(21 citation statements)

References 50 publications

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“…In contrast, all three isoforms bind to receptor RC with similar affinities, but again MC binding has a significant effect ( P value ≤ 0.05) on affinity for IL- (∼4 -fold decrease). Additionally, in agreement with recent studies, 9,15 stoichiometric analysis indicates IL- binds two IL-17RC molecules whilst the other cytokine:receptor complexes studied here have 1 : 1 stoichiometry.…”

Section: Resultssupporting

confidence: 92%

“…Unlabelled and uniformly 15 N, 15 N/ 13 C, 15 N/ 2 H and 15 N/ 13 C/ 2 H labelled samples of mature human IL-17AA and IL-17FF homodimers (residues 24-155 and 31-163 respectively) and IL-17AF hetero-dimers were prepared as described previously. 21…”

Section: Protein Sample Preparationmentioning

confidence: 99%

“…† NMR spectra of the IL-17 dimers were acquired from 350 mL samples of approximately 200 mM monomer IL-17AA, and IL-17FF, and 75-100 mM protomer IL-17AF (only one protomer labelled). NMR spectra of the IL-17 hetero-dimers with macrocycle (MCensemble 369, purchased from WuXi AppTec) were acquired from 350 mL samples of 200 mM 15 N/ 13 C/ 2 H labelled IL-17A in complex with unlabelled IL-17F and 110-200 mM unlabelled IL-17A in complex with 15 N/ 13 C/ 2 H labelled IL-17F and at a saturating concentration of MC (1.5 molar excess). Control experiments (data not presented) were collected to assess the effects of DMSO on the spectra of the various protomers at the maximum amount required to achieve saturation with MC (5% v/v).…”

Section: Nmr Spectroscopymentioning

confidence: 99%

“…Spectra assignments for the apo-IL-17 homo-and hetero-dimers have been reported previously. 21 15 N relaxation data were acquired on a Bruker AV III HD 600 MHz spectrometer using in-house written, standard trosy based T 1 , T 2 and NOE experiments. 25,26 All NMR data were processed using NMRPipe 27 with linear prediction used to extend the effective acquisition times by up to 2-fold in nitrogen in regular sampled data.…”

Section: Nmr Spectroscopymentioning

confidence: 99%

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Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

et al. 2023

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Section: Resultssupporting

confidence: 92%

Section: Protein Sample Preparationmentioning

confidence: 99%

Section: Nmr Spectroscopymentioning

confidence: 99%

Section: Nmr Spectroscopymentioning

confidence: 99%

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Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

et al. 2023

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“…In addition to IL‐17A, IL‐17RA has been shown as a shared receptor for other IL‐17 members such as IL‐17B/C/D/E/F, but it exhibits a >100‐fold higher affinity for IL‐17A than others 9,10 . IL‐17A recognition by the extracellular domain (ECD) of IL‐17RA on monocyte surface can trigger homotypic or heterotypic IL‐17RA/IL17RC dimerization in cytoplasm, which drives the formation of the IL‐17 signalosome to potentiate signaling 11 . Currently, crystal structure is available for IL‐17RA/IL‐17A complex, 12 in which homodimeric IL‐17A dimers displayed a cystine‐knot fold with two intramolecular disulfide bridges, while the functional ECD domain of IL‐17RA is comprised of two immunoglobulin‐like subdomains D1 and D2, which co‐define an active pocket for IL‐17A to bind.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling and rational design of disulfide‐stapled self‐inhibitory peptides to target IL‐17A/IL‐17RA interaction

Huang

Zhou

Pan

et al. 2023

J of Molecular Recognition

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Interleukin‐17A (IL‐17A) is a pro‐inflammatory cytokine implicated in diverse autoimmune and inflammatory disorders such as psoriasis and Kawasaki disease. Mature IL‐17A is a homodimer that binds to the extracellular type‐III fibronectin D1:D2‐dual domain of its cognate IL‐17 receptor A (IL‐17RA). In this study, we systematically examined the structural basis, thermodynamics property, and dynamics behavior of IL‐17RA/IL‐17A interaction and computationally identified two continuous hotspot regions separately from different monomers of IL‐17A homodimer that contribute significantly to the interaction, namely I‐shaped and U‐shaped segments, thus rendered as a peptide‐mediated protein–protein interaction (PmPPI). Self‐inhibitory peptides (SIPs) are derived from the two segments to disrupt IL‐17RA/IL‐17A interaction by competitively rebinding to the IL‐17A‐binding pocket on IL‐17RA surface, which, however, only have a weak affinity and low specificity for IL‐17RA due to lack of the context support of intact IL‐17A protein, thus exhibiting a large flexibility and intrinsic disorder when splitting from the protein context and incurring a considerable entropy penalty when rebinding to IL‐17RA. The U‐shaped segment is further extended, mutated and stapled by a disulfide bridge across its two strands to obtain a number of double‐stranded cyclic SIPs, which are partially ordered and conformationally similar to their native status at IL‐17RA/IL‐17A complex interface. Experimental fluorescence polarization assays substantiate that the stapling can moderately or considerably improve the binding affinity of U‐shaped segment‐derived peptides by 2–5‐fold. In addition, computational structural modeling also reveals that the stapled peptides can bind in a similar mode with the native crystal conformation of U‐shaped segment in IL‐17RA pocket, where the disulfide bridge is out of the pocket for avoiding intervene of the peptide binding.

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Gingerenone A Attenuates Ulcerative Colitis via Targeting IL‐17RA to Inhibit Inflammation and Restore Intestinal Barrier Function

Liang,

Dai,

Liu

et al. 2024

Advanced Science

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Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti‐inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL‐17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL‐17RA protein through pull‐down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus‐mediated IL‐17RA/Act1 knock‐down or GA co‐treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS‐induced inflammation and barrier dysfunction, suggesting a critical role of IL‐17RA signaling for GA‐mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL‐17RA to inhibit inflammatory signaling activation.

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IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling

Cited by 15 publications

References 50 publications

Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

Molecular modeling and rational design of disulfide‐stapled self‐inhibitory peptides to target IL‐17A/IL‐17RA interaction

Gingerenone A Attenuates Ulcerative Colitis via Targeting IL‐17RA to Inhibit Inflammation and Restore Intestinal Barrier Function

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