title: Membrane-proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-disulfide isomerase.
abstract: A disintegrin and metalloprotease-17 (ADAM17) is a major sheddase responsible for the regulation of a wide range of biological processes, like cellular differentiation, regeneration, or cancer progression. Hitherto, the mechanism regulating the enzymatic activity of ADAM17 is poorly understood. Recently, protein-disulfide isomerase (PDI) was shown to interact with ADAM17 and to down-regulate its enzymatic activity. Here we demonstrate by NMR spectroscopy and tandem-mass spectrometry that PDI directly interacts with the membrane-proximal domain (MPD), a domain of ADAM17 involved in its dimerization and substrate recognition. PDI catalyzes an isomerization of disulfide bridges within the thioredoxin motif C600XXC603 of the MPD and results in a drastic structural change between an active open state and an inactive closed conformation. This conformational change of the MPD putatively acts as a molecular switch, facilitating a global reorientation of the extracellular domains in ADAM17 and regulating its shedding activity.
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Düsterhöft
authors.forename: Sascha
authors.initials: S
authors.lastname: Jung
authors.forename: Chien-Wen
authors.initials: CW
authors.lastname: Hung
authors.forename: Andreas
authors.initials: A
authors.lastname: Tholey
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sönnichsen
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Inken
authors.initials: I
authors.lastname: Lorenzen
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry* / Q000378:metabolism*; D000072198:ADAM17 Protein; D002462:Cell Membrane / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D019704:Protein Disulfide-Isomerases; D003545:Cysteine