Crystal Structure of Interleukin-21 Receptor (IL-21R) Bound to IL-21 Reveals That Sugar Chain Interacting with WSXWS Motif Is Integral Part of IL-21R
Crystal Structure of Interleukin-21 Receptor (IL-21R) Bound to IL-21 Reveals That Sugar Chain Interacting with WSXWS Motif Is Integral Part of IL-21R
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DOI：
10.1074/jbc.m111.311084
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发表时间：
2012-03-16
影响因子：
4.8
通讯作者：
Hartmann, Rune
中科院分区：
文献类型：
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作者：
Hamming, Ole J.;Kang, Lishan;Hartmann, Rune
IL-21是一种I类细胞因子，对先天性和适应性免疫应答发挥多效性作用。它通过由IL-21受体（IL-21 R）和共同γ链组成的异二聚体受体复合物发出信号。I类细胞因子受体的标志是I类细胞因子受体特征基序（WSXWS）。该基序的确切作用尚未确定;然而，它涉及多种功能，包括配体结合、受体内化、正确折叠和输出以及信号转导。此外，已知WXXW基序是C-甘露糖基化的共有序列。在这里，我们提出了IL-21结合IL-21 R的晶体结构，并揭示了IL-21 R的WSXWS基序是C-甘露糖基化的第一个色氨酸。我们进一步证明，糖链桥的两个纤连蛋白结构域，构成IL-21 R的胞外结构域和锚定在WSXWS基序通过广泛的氢键网络，包括甘露糖基化。因此，聚糖将V形受体转化为A形框架。这一发现提供了一个新的结构解释的作用，I类细胞因子的签名基序。
IL-21 is a class I cytokine that exerts pleiotropic effects on both innate and adaptive immune responses. It signals through a heterodimeric receptor complex consisting of the IL-21 receptor (IL-21R) and the common gamma-chain. A hallmark of the class I cytokine receptors is the class I cytokine receptor signature motif (WSXWS). The exact role of this motif has not been determined yet; however, it has been implicated in diverse functions, including ligand binding, receptor internalization, proper folding, and export, as well as signal transduction. Furthermore, the WXXW motif is known to be a consensus sequence for C-mannosylation. Here, we present the crystal structure of IL-21 bound to IL-21R and reveal that the WSXWS motif of IL-21R is C-mannosylated at the first tryptophan. We furthermore demonstrate that a sugar chain bridges the two fibronectin domains that constitute the extracellular domain of IL-21R and anchors at the WSXWS motif through an extensive hydrogen bonding network, including mannosylation. The glycan thus transforms the V-shaped receptor into an A-frame. This finding offers a novel structural explanation of the role of the class I cytokine signature motif.