2019, Wißbrock, Amelie, Goradia, Nishit, Kumar, Amit, Paul George, Ajay Abisheck, Kühl, Toni, Bellstedt, Peter, Ramachandran, Ramadurai, Hoffmann, Patrick, Galler, Kerstin, Popp, Jürgen, Neugebauer, Ute, Hampel, Kornelia, Zimmermann, Bastian, Adam, Susanne, Wiendl, Maximilian, Krönke, Gerhard, Hamza, Iqbal, Heinemann, Stefan H., Frey, Silke, Hueber, Axel J., Ohlenschläger, Oliver, Imhof, Diana

Cytokines 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.