The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties
Abstract IL-17A and IL-17F are prominent members of the IL-17 family of cytokines that regulates both innate and adaptive immunity. IL-17A has been implicated in chronic inflammatory and autoimmune diseases, and anti-IL-17A antibodies have shown remarkable clinical efficacy in psoriasis and psoriati...
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2017
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oai:doaj.org-article:62586932f66c4a62852c9be2789af9d42021-12-02T15:05:27ZThe human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties10.1038/s41598-017-08360-92045-2322https://doaj.org/article/62586932f66c4a62852c9be2789af9d42017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08360-9https://doaj.org/toc/2045-2322Abstract IL-17A and IL-17F are prominent members of the IL-17 family of cytokines that regulates both innate and adaptive immunity. IL-17A has been implicated in chronic inflammatory and autoimmune diseases, and anti-IL-17A antibodies have shown remarkable clinical efficacy in psoriasis and psoriatic arthritis patients. IL-17A and IL-17F are homodimeric cytokines that can also form the IL-17A/F heterodimer whose precise role in health and disease remains elusive. All three cytokines signal through the assembly of a ternary complex with the IL-17RA and IL-17RC receptors. Here we report the X-ray analysis of the human IL-17A/F heterodimer that reveals a two-faced cytokine closely mimicking IL-17A as well as IL-17F. We also present the crystal structure of its complex with the IL-17RA receptor. Unexpectedly in view of the much higher affinity of this receptor toward IL-17A, we find that IL-17RA is bound to the “F-face” of the heterodimer in the crystal. Using site-directed mutagenesis, we then demonstrate that IL-17RA can also bind to the “A-face” of IL-17A/F with similar affinity. Further, we show that IL-17RC does not discriminate between the two faces of the cytokine heterodimer either, thus enabling the formation of two topologically-distinct heterotrimeric complexes with potentially different signaling properties.Arnaud GoepfertSylvie LehmannEmmanuelle WirthJean-Michel RondeauNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017) |
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Medicine R Science Q Arnaud Goepfert Sylvie Lehmann Emmanuelle Wirth Jean-Michel Rondeau The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties |
description |
Abstract IL-17A and IL-17F are prominent members of the IL-17 family of cytokines that regulates both innate and adaptive immunity. IL-17A has been implicated in chronic inflammatory and autoimmune diseases, and anti-IL-17A antibodies have shown remarkable clinical efficacy in psoriasis and psoriatic arthritis patients. IL-17A and IL-17F are homodimeric cytokines that can also form the IL-17A/F heterodimer whose precise role in health and disease remains elusive. All three cytokines signal through the assembly of a ternary complex with the IL-17RA and IL-17RC receptors. Here we report the X-ray analysis of the human IL-17A/F heterodimer that reveals a two-faced cytokine closely mimicking IL-17A as well as IL-17F. We also present the crystal structure of its complex with the IL-17RA receptor. Unexpectedly in view of the much higher affinity of this receptor toward IL-17A, we find that IL-17RA is bound to the “F-face” of the heterodimer in the crystal. Using site-directed mutagenesis, we then demonstrate that IL-17RA can also bind to the “A-face” of IL-17A/F with similar affinity. Further, we show that IL-17RC does not discriminate between the two faces of the cytokine heterodimer either, thus enabling the formation of two topologically-distinct heterotrimeric complexes with potentially different signaling properties. |
format |
article |
author |
Arnaud Goepfert Sylvie Lehmann Emmanuelle Wirth Jean-Michel Rondeau |
author_facet |
Arnaud Goepfert Sylvie Lehmann Emmanuelle Wirth Jean-Michel Rondeau |
author_sort |
Arnaud Goepfert |
title |
The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties |
title_short |
The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties |
title_full |
The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties |
title_fullStr |
The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties |
title_full_unstemmed |
The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties |
title_sort |
human il-17a/f heterodimer: a two-faced cytokine with unique receptor recognition properties |
publisher |
Nature Portfolio |
publishDate |
2017 |
url |
https://doaj.org/article/62586932f66c4a62852c9be2789af9d4 |
work_keys_str_mv |
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