CC BY 4.0 UnportedWißbrock, AmelieGoradia, NishitKumar, AmitPaul George, Ajay AbisheckKühl, ToniBellstedt, PeterRamachandran, RamaduraiHoffmann, PatrickGaller, KerstinPopp, JürgenNeugebauer, UteHampel, KorneliaZimmermann, BastianAdam, SusanneWiendl, MaximilianKrönke, GerhardHamza, IqbalHeinemann, Stefan H.Frey, SilkeHueber, Axel J.Ohlenschläger, OliverImhof, Diana2020-01-032020-01-032019https://doi.org/10.34657/85https://oa.tib.eu/renate/handle/123456789/4814Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins.enghttps://creativecommons.org/licenses/by/4.0/610interleukinIL-36inflammatory responseArticle