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

Abstract

Edited by Gianni CesareniKeywords: Metalloprotease ADAM17 EGF-like domain Cysteine-rich domain Membrane-proximal domain Substrate recognition a b s t r a c t A great number of physiological processes are regulated by the release of ectodomains of membrane proteins. A Disintegrin And Metalloprotease 17 (ADAM17) is one of the important enzymes, which mediate this process called shedding. Today, more than 70 substrates of this transmembrane metalloprotease are known. This broad spectrum raises the question how ADAM17 recognizes its substrates specifically. Differently tagged ADAM17 deletion variants were used to demonstrate that exclusively the extracellular domains of ADAM17 are needed for interaction with two of its substrates, the IL-6R and the IL-1RII; whereas the transmembrane-and cytoplasmic-region are dispensable for this process. In the extracellular part solely the membrane-proximal domain of ADAM17 is mandatory for recognition of the two type-I transmembrane proteins, but not for the interaction with the type-II transmembrane molecule TNF-a. Structured summary of protein interactions:IL-6R physically interacts with ADAM17 by anti bait coimmunoprecipitation (View interaction) ADAM17 physically interacts with IL-1RII by anti tag coimmunoprecipitation (View interaction)

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

“…36 Membrane localization of ADAM17 is a prerequisite for its proper function. 37,38 Therefore, we speculated that ADAM17-specific activity in the blood samples of patients with AAV depends on its localization on cell-derived microparticles. Microparticles contain high amounts of lipid rafts, and these cholesterol-rich membrane microdomains are known to harbor a huge variety of signaling molecules, receptors, and proteases, including the mature form of ADAM17.…”

Minimal Interleukin 6 (IL-6) Receptor Stalk Composition for IL-6 Receptor Shedding and IL-6 Classic Signaling

“…Genetic alteration of the ADAM cleavage site of a single substrate seems to be a promising strategy for in vivo analysis. Furthermore, the three-dimensional conformation of the substrate plays a role for ADAM-mediated shedding (13,32,33), which is recognized by the membrane-proximal domain of ADAM17 (36).…”

A Disintegrin and Metalloprotease 17 Dynamic Interaction Sequence, the Sweet Tooth for the Human Interleukin 6 Receptor

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