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Structural insights into the assembly of gp130 family cytokine signaling complexes

By Yi Zhou, Panayiotis E. Stevis, Jing Cao, Kei Saotome, Jiaxi Wu, Arielle Glatman Zaretsky, Sokol Haxhinasto, George D Yancopoulos, Andrew J Murphy, Mark W. Sleeman, William C. Olson, Matthew C. Franklin

Posted 30 Jun 2022
bioRxiv DOI: 10.1101/2022.06.30.496838

The gp130 family cytokine signaling complexes have limited structural information despite their crucial roles in various cellular processes. We determined cryo-EM structures of several complexes of this family, containing full ectodomains of both signaling receptors bound to their respective ligands CNTF, CLCF1, LIF, IL-27, and IL-6. Our structures reveal that gp130 serves as a central receptor by engaging Site 2 of CNTF, CLCF1, LIF, and IL-6, and Site 3 of IL-27 and IL-6. The acute bends at both signaling receptors in all complexes bring the membrane-proximal domains to a ~30 [A] range but with distinct distances and orientations, which might determine biological specificities of these cytokines. We also reveal how CLCF1 engages its secretion chaperone CRLF1. Our data provide valuable insights for therapeutically targeting gp130-mediated signaling.

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