title: gp130 activation is regulated by D2-D3 interdomain connectivity.
abstract: Activation of the IL-6 (interleukin 6) receptor subunit gp130 (glycoprotein 130) has been linked to the formation of complexes with IL-6 and the IL-6 receptor, as well as to gp130 dimerization. However, it has been shown that gp130 is present as a pre-formed dimer, indicating that its activation is not solely dependent on dimerization. Therefore the detailed mechanism of gp130 activation still remains to be deciphered. Recently, deletion mutations of gp130 have been found in inflammatory hepatocellular adenoma. The mutations clustered around one IL-6-binding epitope of gp130 and resulted in a ligand-independent constitutively active gp130. We therefore hypothesized that conformational changes of this particular IL-6-binding epitope precedes gp130 activation. Using a rational structure-based approach we identified for the first time amino acids critical for gp130 activation. We can show that gp130 D2-D3 interdomain connectivity by hydrophobic residues stabilizes inactive gp130 conformation. Conformational destabilization of the EF loop present in domain D2 and disruption of D2-D3 hydrophobic interactions resulted in ligand-independent gp130 activation. Furthermore we show that the N-terminal amino acid residues of domain D1 participate in the activation of the gp130 deletion mutants. Taken together we present novel insights into the molecular basis of the activation of a cytokine receptor signalling subunit.
authors.affiliation: Christian-Albrechts-Universität zu Kiel, Institute of Biochemistry, Rudolf-Höber-Strasse 1, 24118 Kiel, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Schütt
authors.forename: Martin
authors.initials: M
authors.lastname: Zacharias
authors.forename: Nico
authors.initials: N
authors.lastname: Schneider
authors.forename: Silke
authors.initials: S
authors.lastname: Horn
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt-Arras
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology*; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: D050822:Cytokine Receptor gp130