A disintegrin and metalloprotease 17 dynamic interaction sequence, the sweet tooth for the human interleukin 6 receptor.
A disintegrin and metalloprotease 17 (ADAM17) is a major sheddase involved in the regulation of a wide range of biological processes. Key substrates of ADAM17 are the IL-6 receptor (IL-6R) and TNF-α. The extracellular region of ADAM17 consists of a prodomain, a catalytic domain, a disintegrin domain, and a membrane-proximal domain as well as a small stalk region. This study demonstrates that this juxtamembrane segment is highly conserved, α-helical, and involved in IL-6R binding. This process is regulated by the structure of the preceding membrane-proximal domain, which acts as molecular switch of ADAM17 activity operated by a protein-disulfide isomerase. Hence, we have termed the conserved stalk region "Conserved ADAM seventeen dynamic interaction sequence" (CANDIS). Finally, we identified the region in IL-6R that binds to CANDIS. In contrast to the type I transmembrane proteins, the IL-6R, and IL-1RII, CANDIS does not bind the type II transmembrane protein TNF-α, demonstrating fundamental differences in the respective shedding by ADAM17.
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Stefan
S
Düsterhöft
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Katharina
K
Höbel
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Mirja
M
Oldefest
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Juliane
J
Lokau
the CONARIS Research Institute AG, Schauenburgerstr. 116, 24118 Kiel, Germany, and.
Georg H
GH
Waetzig
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Athena
A
Chalaris
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany, the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Christoph
C
Garbers
the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Jürgen
J
Scheller
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Stefan
S
Rose-John
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
Inken
I
Lorenzen
From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany, jgroetzinger@biochem.uni-kiel.de.
Joachim
J
Grötzinger
D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism*; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D017124:Conserved Sequence; D017931:DNA Primers; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D019947:Receptors, Interleukin-6; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
ADAMTS; Enzyme Inactivation; Interleukin; Interleukin Shedding; Protein-Protein Interaction; Redox Regulation; Tumor Necrosis Factor (TNF)