title: A soluble form of the interleukin-6 family signal transducer gp130 is dimerized via a C-terminal disulfide bridge resulting from alternative mRNA splicing.
abstract: Interleukin-6 (IL-6) signaling can be divided into classic signaling (via the membrane-bound IL-6 receptor, IL-6R) and trans-signaling (via the soluble IL-6R, sIL-6R), and both modes of signaling activate cells via a homodimer of the ubiquitously expressed β-receptor glycoprotein 130 (gp130). IL-6 trans-signaling is responsible for most of the pro-inflammatory activities of IL-6 and plays a role in many inflammatory diseases including inflammation-driven cancers. IL-6 trans-signaling can be selectively inhibited by soluble forms of gp130. To date, three forms of sgp130 (full-length sgp130, sgp130-RAPS and sgp130-E10) with different molecular weight have been described, which originate from alternative splicing or alternative polyadenylation of the gp130 mRNA. All these proteins are capable of blocking signaling of the IL-6/sIL-6R complex, albeit with different efficacy. The full length form of sgp130 comprises the domains D1 to D6 and a short unique C-terminus which arises from alternative splicing. In the present study, we analyze the role of a unique cysteine residue (Cys-628) within this C-terminus, which is contained neither in the membrane-bound gp130 nor in the two other sgp130 forms. Full-length sgp130 can form a disulfide-linked dimer via this cysteine residue. These natural sgp130 dimers are absent under reducing conditions or in a sgp130 C628A mutant. Although the disulfide-dimerized sgp130 represents only a small fraction of the total amount of sgp130 and, thus, may appear to be dispensable for the global inhibitory activities of sgp130 in the circulation, it may represent a further possibility to modulate gradients of sgp130 with different properties depending on the local redox potential in a cell- or tissue-dependent manner.
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Wolf
authors.affiliation: CONARIS Research Institute AG, Kiel, Germany.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
authors.affiliation: Non-Clinical Development, Ferring Pharmaceuticals A/S, Copenhagen, Denmark.
authors.forename: Torsten M
authors.initials: TM
authors.lastname: Reinheimer
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Biochemistry, Kiel University, Kiel, Germany. Electronic address: cgarbers@biochem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D050822:Cytokine Receptor gp130 / Q000737:chemistry* / Q000235:genetics*; D004220:Disulfides / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D004220:Disulfides; D012333:RNA, Messenger; D050822:Cytokine Receptor gp130
keywords: Gp130; IL-6R; Interleukin-6; Sgp130; Trans-signaling