Structural basis of ? chain family receptor sharing at the membrane level

• 成果类型: Article
• 署名作者: Cai, Tiantian; Capello, Rachel Lenoir; Pi, Xiong; Wu, Hao; Chou, James J. J.
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Chinese Academy of Sciences; Hefei Institutes of Physical Science, CAS; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9668
• DOI: 10.1126/science.add1219
• 发表日期: 2023-08-04
• 页码: 569-576
• 关键词: transmembrane domain; computational design; gamma(c) family; t-cells; mutations; cytokines; biology; interleukin-2; architecture; activation

摘要

Common ? chain (?c) cytokine receptors, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, are activated upon engagement with a common ?c receptor (CD132) by concomitant binding of their ectodomains to an interleukin. In this work, we find that direct interactions between the transmembrane domains (TMDs) of both the ?c and the interleukin receptors (ILRs) are also required for receptor activation. Moreover, the same ?c TMD can specifically recognize multiple ILR TMDs of diverse sequences within the family. Heterodimer structures of ?c TMD bound to IL-7 and IL-9 receptor TMDs-determined in a lipid bilayer-like environment by nuclear magnetic resonance spectroscopy-reveal a conserved knob-into-hole mechanism of recognition that mediates receptor sharing within the membrane. Thus, signaling in the ?c receptor family requires specific heterotypic interactions of the TMDs.