Differential activity and selectivity of N-terminal modified CXCL12 chemokines at the CXCR4 and ACKR3 receptors.
Differential activity and selectivity of N-terminal modified CXCL12 chemokines at the CXCR4 and ACKR3 receptors.
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N 端修饰的 CXCL12 趋化因子对 CXCR4 和 ACKR3 受体的差异活性和选择性。
DOI：
10.1002/jlb.2ma0320-383rr
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发表时间：
2020-06
影响因子：
5.5
通讯作者：
Levoye A
中科院分区：
文献类型：
--
作者：
Jaracz-Ros A;Bernadat G;Cutolo P;Gallego C;Gustavsson M;Cecon E;Baleux F;Kufareva I;Handel TM;Bachelerie F;Levoye A
趋化因子通过对7种跨膜受体的作用，在许多生理和病理过程中发挥关键作用。趋化因子的n端结构域是信号传导的关键决定因素，它通过与受体的TM螺旋形成的口袋结合，可以成为蛋白水解加工的目标。这种调节机制的一个典型例子是CXCL12的自然加工，产生缺乏前两个n端残基的趋化因子变体。虽然这些截断的变体作为CXCL12的典型G蛋白偶联受体CXCR4的拮抗剂，但它们是非典型趋化因子受体3 （ACKR3/CXCR7）的激动剂，这表明在CXCL12与其两个受体之间形成的复合物中存在不同的结构决定因素。最近的分析表明，CXCL12 n端首先与ACKR3的TM螺旋结合，然后是受体n端包裹在趋化因子核心周围。在这里，我们通过比较CXCL12取代或n端截断变体对CXCR4和ACKR3的活性，研究了ACKR3-CXCL12相互作用的第一阶段。我们发现，修饰趋化因子的前两个n端残基（K1R或P2G）不会改变CXCL12激活ACKR3的能力。我们的研究结果还发现K1R变体是CXCR4的G蛋白偏向激动剂。ACKR3与CXCL12或P2G变体形成复合物的分子动力学模拟比较发现，CXCL12的n端3-5残基与受体的TM螺旋2、6和7形成的口袋之间的相互作用是ACKR3激活的关键决定因素。CXCL12的三到五个n端残基对于与ACKR3结合至关重要，并且是激活CXCR4和ACKR3所必需的
Chemokines play critical roles in numerous physiological and pathological processes through their action on seven-transmembrane (TM) receptors. The N-terminal domain of chemokines, which is a key determinant of signaling via its binding within a pocket formed by receptors’ TM helices, can be the target of proteolytic processing. An illustrative case of this regulatory mechanism is the natural processing of CXCL12 that generates chemokine variants lacking the first two N-terminal residues. While such truncated variants behave as antagonists of CXCR4, the canonical G protein-coupled receptor of CXCL12, they are agonists of the atypical chemokine receptor 3 (ACKR3/CXCR7), suggesting the implication of different structural determinants in the complexes formed between CXCL12 and its two receptors. Recent analyses have suggested that the CXCL12 N-terminus first engages the TM helices of ACKR3 followed by the receptor N-terminus wrapping around the chemokine core. Here we investigated the first stage of ACKR3-CXCL12 interactions by comparing the activity of substituted or N-terminally truncated variants of CXCL12 toward CXCR4 and ACKR3. We showed that modification of the first two N-terminal residues of the chemokine (K1R or P2G) does not alter the ability of CXCL12 to activate ACKR3. Our results also identified the K1R variant as a G protein-biased agonist of CXCR4. Comparative molecular dynamics simulations of the complexes formed by ACKR3 either with CXCL12 or with the P2G variant identified interactions between the N-terminal 3–5 residues of CXCL12 and a pocket formed by receptor’s TM helices 2, 6 and 7 as critical determinants for ACKR3 activation. Three to five N-terminal residues of CXCL12 are critical for binding to ACKR3 and required for activation of both CXCR4 and ACKR3