Extracellular Juxtamembrane Segment of ADAM17 Interacts with Membranes and Is Essential for Its Shedding Activity.
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.
Stefan
S
Düsterhöft
Matthias
M
Michalek
Department of Dermatology and Allergology, University Hospital Schleswig-Holstein , Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
Felix
F
Kordowski
Mirja
M
Oldefest
Department of Dermatology and Allergology, University Hospital Schleswig-Holstein , Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
Anselm
A
Sommer
Jona
J
Röseler
Department of Dermatology and Allergology, University Hospital Schleswig-Holstein , Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
Karina
K
Reiss
Joachim
J
Grötzinger
Inken
I
Lorenzen
D051722:ADAM Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D013379:Substrate Specificity
D008051:Lipid Bilayers; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse