The N-terminal region of the atypical chemokine receptor ACKR2 is a key determinant of ligand binding.
The N-terminal region of the atypical chemokine receptor ACKR2 is a key determinant of ligand binding.
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DOI：
10.1074/jbc.m113.534545
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发表时间：
2014-05-02
期刊：
影响因子：
--
通讯作者：
Graham GJ
中科院分区：
文献类型：
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作者：
Hewit KD;Fraser A;Nibbs RJ;Graham GJ
背景：ACKR2是一种非典型的趋化因子受体，在生物学上与传统的趋化因子受体不同。结果：N-末端硫酸化酪氨酸基序对于ACKR2的配体结合是必需的。结论：ACKR 2与配体结合的结构/功能基础与常规趋化因子受体相似。意义：ACKR2 N-末端肽可能在炎症病理学中作为泛趋化因子阻断剂治疗有用。非典型趋化因子受体ACKR2是趋化因子驱动的炎症反应的关键调节因子，并通过结合、内化和降解炎性CC-趋化因子起作用。ACKR2显示配体结合的混杂性，并且能够与多达14种不同的炎性CC趋化因子相互作用。尽管其突出的生物学作用，但对调节配体结合的ACKR2内的结构/功能关系知之甚少。在这里，我们证明了一个保守的酪氨酸基序在N末端的ACKR2是必不可少的配体结合，内化和清除。此外，我们表明，硫酸化的这个主题有助于配体内化。此外，衍生自该区域的肽能够结合炎性趋化因子并抑制它们与其同源信号传导受体的相互作用。重要的是，该肽仅在硫酸化形式下具有活性，进一步证实了硫酸化酪氨酸对功能的重要性。最后，我们证明了细菌蛋白酶，葡萄球菌蛋白酶A，可以切割N末端的ACKR2和抑制其配体内化活性。总体而言，这些结果为ACKR 2中负责配体结合的结构基序的性质提供了新的线索。该研究还强调了ACKR2衍生的N-末端肽具有潜在的治疗意义。
Background: ACKR2 is an atypical chemokine receptor that is biologically distinct from conventional chemokine receptors. Results: An N-terminal sulfated tyrosine motif is essential for ligand binding by ACKR2. Conclusion: The structure/function basis for ligand binding by ACKR2 is similar to that of conventional chemokine receptors. Significance: ACKR2 N-terminal peptides may be therapeutically useful as pan-chemokine blockers in inflammatory pathologies. The atypical chemokine receptor, ACKR2 is a pivotal regulator of chemokine-driven inflammatory responses and works by binding, internalizing, and degrading inflammatory CC-chemokines. ACKR2 displays promiscuity of ligand binding and is capable of interacting with up to 14 different inflammatory CC-chemokines. Despite its prominent biological role, little is known about the structure/function relationship within ACKR2, which regulates ligand binding. Here we demonstrate that a conserved tyrosine motif at the N terminus of ACKR2 is essential for ligand binding, internalization, and scavenging. In addition we demonstrate that sulfation of this motif contributes to ligand internalization. Furthermore, a peptide derived from this region is capable of binding inflammatory chemokines and inhibits their interaction with their cognate signaling receptors. Importantly, the peptide is only active in the sulfated form, further confirming the importance of the sulfated tyrosines for function. Finally, we demonstrate that the bacterial protease, staphopain A, can cleave the N terminus of ACKR2 and suppress its ligand internalization activity. Overall, these results shed new light on the nature of the structural motifs in ACKR2 that are responsible for ligand binding. The study also highlights ACKR2-derived N-terminal peptides as being of potential therapeutic significance.