Structural insights into the assembly of gp130 family cytokine signaling complexes

Abstract

The interleukin-6 (IL-6) family cytokines signal through gp130 receptor homodimerization or heterodimerization with a second signaling receptor and play crucial roles in various cellular processes. We determined cryo–electron microscopy structures of five signaling complexes of this family, containing full receptor ectodomains bound to their respective ligands ciliary neurotrophic factor, cardiotrophin-like cytokine factor 1 (CLCF1), leukemia inhibitory factor, IL-27, and IL-6. Our structures collectively reveal similarities and differences in the assembly of these complexes. The acute bends at both signaling receptors in all complexes bring the membrane-proximal domains to a ~30 angstrom range but with distinct distances and orientations. We also reveal how CLCF1 engages its secretion chaperone cytokine receptor–like factor 1. Our data provide valuable insights for therapeutically targeting gp130-mediated signaling.

Engineered interleukin-6-derived cytokines recruit artificial receptor complexes and disclose CNTF signaling via the OSMR

“…1 A ) ( 13 , 18 , 27 ). The cytokimera GIL-6 and GIO-6 are designed to specifically form α-receptor-dependent tetrameric complexes consisting of GIL-6:IL-6R:gp130:LIFR, GIO-6:IL-6R:gp130:LIFR and GIO-6:IL-6R:gp130:LIFR ( 11 , 13 , 28 , 29 , 30 , 31 , 32 , 33 ) ( Fig. 1 A ).…”

Exogenous l-fucose attenuates neuroinflammation induced by lipopolysaccharide

“…To gain structural insights on the core fucosylation on gp130, we built a 3D structural model of N -glycosylated IL-6–sIL-6R–gp130 complex based on the cryo-EM structure of human IL-6–sIL-6R/–gp130 complex ( Fig. S4 ) ( 52 ). Gp130 is heavily glycosylated, especially N -glycans on N43, N61, N83, N131, and N157, which are clustered in close proximity with the other gp130 and IL-6 molecules.…”

“…Homology modeling of murine IL-6, sIL-6R, and gp130 was performed using SWISS-MODEL ( 99 ), and the template was the cryo-EM structure of human IL-6–sIL-6R–gp130 hexametric complex with stoichiometry of 2:2:2 (Protein Data Bank ID: 8D82 ) ( 52 ). Glycan Modeler tool in CHARMM-GUI ( 100 ) was used to build a 3D structural model of N -glycosylated murine IL-6–sIL-6R–gp130 complex.…”

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy

“… 41 All domains were rigidly fit to the cryo-reconstruction in (see, Zhou Y, et al). 42 To generate the homology model of JAK2, structures of JAK2 domains FERM-SH2 [PDB ID: 6E2Q], 43 pseudokinase [PDB ID: 4FVQ], 44 and kinase with AZD1480 [PDB ID: 2XA4] 45 were aligned on the JAK1 dimeric complex [PDB ID: 7T6F]. 46 A composite of the JAK2 domains was submitted to SWISS-MODEL 47 to fill in missing gaps between structures with the dimeric JAK1 structure as a guide.…”