Extracellular Juxtamembrane Segment of ADAM17 Interacts with Membranes and Is Essential for Its Shedding Activity

Abstract

A wide variety of biological processes including differentiation, regeneration, and cancer progression are regulated by shedding of membrane-anchored proteins. One of the major sheddases is A Disintegrin And Metalloprotease-17 (ADAM17) whose extracellular region consists of a pro-, a catalytic, a disintegrin-, and a membrane-proximal domain (MPD) as well as a short juxtamembrane segment of 17 amino acid residues that has been named "Conserved ADAM-seventeeN Dynamic Interaction Sequence" (CANDIS). This segment is involved in substrate recognition. Key mediators of inflammation including interleukin-6 receptor (IL-6R) and tumor necrosis factor (TNF-α) are substrates of ADAM17. The shedding activity of ADAM17 is regulated by the conformation of the membrane-proximal domain preceding the CANDIS segment. Here, we show that CANDIS, besides being involved in substrate recognition, is able to interact with lipid bilayers in vitro and that this property could be involved in regulating ADAM17 shedding activity.

Association Study Between Promoter Polymorphisms of ADAM17 and Progression of Sepsis

“…ADAM17, also known as TACE, is initially recognized to convert transmembrane TNF-α to its soluble form, which is recognized as a significant immune regulatory factor contributing to sepsis pathogenesis [41][42][43]. In addition to TNF-α, a wide variety of over 75 substrates are shed by ADAM17, including IL-6R, CX3CL1, L-selectin and ICAM-1 [11][12][13]44]. CX3CL1 can also be generated by ADAM17-dependent cleavage and ectodomain shedding under pro-inflammatory conditions that mediates leukocyte transmigration out of the bloodstream to the inflammation site [45,46].…”

How membrane asymmetry regulates ADAM17 sheddase function

“…The ADAM17 stalk region, also named CANDIS (Conserved ADAM-SeventeeN Dynamic Interaction Sequence), has recently been found to represent a membrane-interacting amphipathic helix that is also required for sheddase function 6 . The combined data now lead to a 2-step model for ADAM17-mediated shedding which shares similarities with the activation of intracellular proteins including the accessory HIV-1 protein Nef.…”

LRP1 Controls TNF Release via the TIMP-3/ADAM17 Axis in Endotoxin-Activated Macrophages

“…ADAM17 activity is rapidly induced in response to LPS or PMA stimulation, without any increase in its cell surface expression. Many mechanisms have been proposed to explain this phenomenon, including compartmentalization of the enzyme in membrane microdomains (7,8) and conformational changes in the ADAM17 ectodomain (9,10), postulated to involve protein disulfide isomerase (10,11) and/or interaction of juxtamembrane regions of ADAM17 with the lipid bilayer (12). Phosphorylation of the intracellular domain of ADAM17 affects activity in some cases (13)(14)(15)(16)(17), but not all (9).…”