| Structural highlights
Disease
[IL17F_HUMAN] Defects in IL17F are the cause of familial candidiasis type 6 (CANDF6) [MIM:613956]. CANDF6 is a rare disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans.[1] [I17RC_HUMAN] Chronic mucocutaneous candidiasis. The disease is caused by mutations affecting the gene represented in this entry.
Function
[IL17F_HUMAN] Stimulates the production of other cytokines such as IL-6, IL-8 and granulocyte colony-stimulating factor, and can regulate cartilage matrix turnover. Stimulates PBMC and T-cell proliferation. Inhibits angiogenesis. [I17RC_HUMAN] Receptor for IL17A and IL17F homodimers as part of a heterodimeric complex with IL17RA (PubMed:16785495). Receptor for the heterodimer formed by IL17A and IL17B as part of a heterodimeric complex with IL17RA (PubMed:18684971). Has also been shown to be the cognate receptor for IL17F and to bind IL17A with high affinity without the need for IL17RA (PubMed:17911633). Activation of IL17RC leads to induction of expression of inflammatory chemokines and cytokines such as CXCL1 (PubMed:16785495).[2] [3] [4] Receptor for both IL17A and IL17F.[5] Does not bind IL17A or IL17F.[6] Does not bind IL17A or IL17F.[7] Receptor for both IL17A and IL17F.[8]
Publication Abstract from PubMed
Interleukin-17A (IL-17A), IL-17F, and IL-17A/F heterodimers are key cytokines of the innate and adaptive immune response. Dysregulation of the IL-17 pathway contributes to immune pathology, and it is therefore important to elucidate the molecular mechanisms that govern IL-17 recognition and signaling. The receptor IL-17RC is thought to act in concert with IL-17RA to transduce IL-17A-, IL-17F-, and IL-17A/F-mediated signals. We report the crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F. In contrast to the expected model, we found that IL-17RC formed a symmetrical 2:1 complex with IL-17F, thus competing with IL-17RA for cytokine binding. Using biophysical techniques, we showed that IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC, suggesting the possibility of IL-17RA-independent IL-17 signaling pathways. The crystal structure of the IL-17RC:IL-17F complex provides a structural basis for IL-17F signaling through IL-17RC, with potential therapeutic applications for respiratory allergy and inflammatory bowel diseases.
Structural Analysis Reveals that the Cytokine IL-17F Forms a Homodimeric Complex with Receptor IL-17RC to Drive IL-17RA-Independent Signaling.,Goepfert A, Lehmann S, Blank J, Kolbinger F, Rondeau JM Immunity. 2020 Mar 17;52(3):499-512.e5. doi: 10.1016/j.immuni.2020.02.004. PMID:32187518[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L, Chrabieh M, Audry M, Gumbleton M, Toulon A, Bodemer C, El-Baghdadi J, Whitters M, Paradis T, Brooks J, Collins M, Wolfman NM, Al-Muhsen S, Galicchio M, Abel L, Picard C, Casanova JL. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011 Apr 1;332(6025):65-8. doi: 10.1126/science.1200439. Epub 2011 Feb, 24. PMID:21350122 doi:10.1126/science.1200439
- ↑ Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol. 2006 Jul 1;177(1):36-9. doi: 10.4049/jimmunol.177.1.36. PMID:16785495 doi:http://dx.doi.org/10.4049/jimmunol.177.1.36
- ↑ Kuestner RE, Taft DW, Haran A, Brandt CS, Brender T, Lum K, Harder B, Okada S, Ostrander CD, Kreindler JL, Aujla SJ, Reardon B, Moore M, Shea P, Schreckhise R, Bukowski TR, Presnell S, Guerra-Lewis P, Parrish-Novak J, Ellsworth JL, Jaspers S, Lewis KE, Appleby M, Kolls JK, Rixon M, West JW, Gao Z, Levin SD. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J Immunol. 2007 Oct 15;179(8):5462-73. PMID:17911633
- ↑ Wright JF, Bennett F, Li B, Brooks J, Luxenberg DP, Whitters MJ, Tomkinson KN, Fitz LJ, Wolfman NM, Collins M, Dunussi-Joannopoulos K, Chatterjee-Kishore M, Carreno BM. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol. 2008 Aug 15;181(4):2799-805. doi: 10.4049/jimmunol.181.4.2799. PMID:18684971 doi:http://dx.doi.org/10.4049/jimmunol.181.4.2799
- ↑ Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol. 2006 Jul 1;177(1):36-9. doi: 10.4049/jimmunol.177.1.36. PMID:16785495 doi:http://dx.doi.org/10.4049/jimmunol.177.1.36
- ↑ Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol. 2006 Jul 1;177(1):36-9. doi: 10.4049/jimmunol.177.1.36. PMID:16785495 doi:http://dx.doi.org/10.4049/jimmunol.177.1.36
- ↑ Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol. 2006 Jul 1;177(1):36-9. doi: 10.4049/jimmunol.177.1.36. PMID:16785495 doi:http://dx.doi.org/10.4049/jimmunol.177.1.36
- ↑ Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol. 2006 Jul 1;177(1):36-9. doi: 10.4049/jimmunol.177.1.36. PMID:16785495 doi:http://dx.doi.org/10.4049/jimmunol.177.1.36
- ↑ Goepfert A, Lehmann S, Blank J, Kolbinger F, Rondeau JM. Structural Analysis Reveals that the Cytokine IL-17F Forms a Homodimeric Complex with Receptor IL-17RC to Drive IL-17RA-Independent Signaling. Immunity. 2020 Mar 17;52(3):499-512.e5. doi: 10.1016/j.immuni.2020.02.004. PMID:32187518 doi:http://dx.doi.org/10.1016/j.immuni.2020.02.004
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