Structural insights into the assembly of gp130 family cytokine signaling complexes

• Published in: Science advances Vol. 9; no. 11; p. eade4395
• Main Authors: Zhou, Yi, Stevis, Panayiotis E, Cao, Jing, Saotome, Kei, Wu, Jiaxi, Glatman Zaretsky, Arielle, Haxhinasto, Sokol, Yancopoulos, George D, Murphy, Andrew J, Sleeman, Mark W, Olson, William C, Franklin, Matthew C
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 17.03.2023
• Subjects: Antigens, CD - metabolism; Biomedicine and Life Sciences; Cryoelectron Microscopy; Cytokine Receptor gp130 - metabolism; Cytokines - metabolism; Immunology; Interleukin-6 - metabolism; Leukemia Inhibitory Factor Receptor alpha Subunit - metabolism; Membrane Glycoproteins - metabolism; SciAdv r-articles; Structural Biology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.ade4395

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.