The membrane-proximal domain of A Disintegrin and Metalloprotease 17 (ADAM17) is responsible for recognition of the interleukin-6 receptor and interleukin-1 receptor II

► The transmembrane protease ADAM17 recognizes more than 70 substrates. ► The minimal requirement for recognition of two substrates was identified. ► The IL-1RII and the IL-6R are recognized by the membrane-proximal domain. ► In this respect the transmembrane- and cytoplasmic regions are dispensable. ► No interaction between TNF-α and the membrane-proximal domain has been detected.