Structural Snapshots of Full-Length Jak1, a Transmembrane gp130/IL-6/IL-6Rα Cytokine Receptor Complex, and the Receptor-Jak1 Holocomplex

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• 作者：Patrick J. Lupardus¹ ; ⁶ ; Georgios Skiniotis² ; ⁵ ; ⁶ ; Amanda J. Rice² ; Christoph Thomas¹ ; Suzanne Fischer¹ ; Thomas Walz² ; ³ ; K. Christopher Garcia¹ ; ⁴ ; ^{kcgarcia@stanford.edu}
• 刊名：Structure
• 出版年：2011
• 出版时间：12 January 2011
• 年：2011
• 卷：19
• 期：1
• 页码：45-55
• 全文大小：1410 K

文摘

Summary

The shared cytokine receptor gp130 signals as a homodimer or heterodimer through activation of Janus kinases (Jaks) associated with the receptor intracellular domains. Here, we reconstitute, in parts and whole, the full-length gp130 homodimer in complex with the cytokine interleukin-6 (IL-6), its alpha receptor (IL-6Rα) and Jak1, for electron microscopy imaging. We find that the full-length gp130 homodimer complex has intimate interactions between the trans- and juxtamembrane segments of the two receptors, appearing to form a continuous connection between the extra- and intracellular regions. 2D averages and 3D reconstructions of full-length Jak1 reveal a three lobed structure comprising FERM-SH2, pseudokinase, and kinase modules possessing extensive intersegmental flexibility that likely facilitates allosteric activation. Single-particle imaging of the gp130/IL-6/IL-6Rα/Jak1 holocomplex shows Jak1 associated with the membrane proximal intracellular regions of gp130, abutting the would-be inner leaflet of the cell membrane. Jak1 association with gp130 is enhanced by the presence of a membrane environment.