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The dimeric form of CXCL12 binds to atypical chemokine receptor 1
Science Signaling ( IF 6.7 ) Pub Date : 2021-08-17 , DOI: 10.1126/scisignal.abc9012
Julia C Gutjahr 1 , Kyler S Crawford 2 , Davin R Jensen 2 , Prachi Naik 1 , Francis C Peterson 2 , Guerric P B Samson 3 , Daniel F Legler 3, 4 , Johan Duchene 5 , Christopher T Veldkamp 6 , Antal Rot 1, 5, 7 , Brian F Volkman 2
Affiliation  

The pleiotropic chemokine CXCL12 is involved in diverse physiological and pathophysiological processes, including embryogenesis, hematopoiesis, leukocyte migration, and tumor metastasis. It is known to engage the classical receptor CXCR4 and the atypical receptor ACKR3. Differential receptor engagement can transduce distinct cellular signals and effects as well as alter the amount of free, extracellular chemokine. CXCR4 binds both monomeric and the more commonly found dimeric forms of CXCL12, whereas ACKR3 binds monomeric forms. Here, we found that CXCL12 also bound to the atypical receptor ACKR1 (previously known as Duffy antigen/receptor for chemokines or DARC). In vitro nuclear magnetic resonance spectroscopy and isothermal titration calorimetry revealed that dimeric CXCL12 bound to the extracellular N terminus of ACKR1 with low nanomolar affinity, whereas the binding affinity of monomeric CXCL12 was orders of magnitude lower. In transfected MDCK cells and primary human Duffy-positive erythrocytes, a dimeric, but not a monomeric, construct of CXCL12 efficiently bound to and internalized with ACKR1. This interaction between CXCL12 and ACKR1 provides another layer of regulation of the multiple biological functions of CXCL12. The findings also raise the possibility that ACKR1 can bind other dimeric chemokines, thus potentially further expanding the role of ACKR1 in chemokine retention and presentation.



中文翻译:

CXCL12 的二聚体形式与非典型趋化因子受体 1 结合

多效趋化因子 CXCL12 参与多种生理和病理生理过程,包括胚胎发生、造血、白细胞迁移和肿瘤转移。已知与经典受体 CXCR4 和非典型受体 ACKR3 结合。不同的受体参与可以转导不同的细胞信号和效应,并改变游离的细胞外趋化因子的数量。CXCR4 结合单体和更常见的二聚体形式的 CXCL12,而 ACKR3 结合单体形式。在这里,我们发现 CXCL12 还与非典型受体 ACKR1(以前称为 Duffy 抗原/趋化因子受体或 DARC)结合。体外核磁共振波谱和等温滴定量热法显示二聚体 CXCL12 以低纳摩尔亲和力与 ACKR1 的细胞外 N 末端结合,而单体 CXCL12 的结合亲和力低几个数量级。在转染的 MDCK 细胞和原代人 Duffy 阳性红细胞中,CXCL12 的二聚体而非单体构建体有效地与 ACKR1 结合并内化。CXCL12 和 ACKR1 之间的这种相互作用为 CXCL12 的多种生物学功能提供了另一层调节。这些发现还提出了 ACKR1 可以结合其他二聚体趋化因子的可能性,因此可能进一步扩大 ACKR1 在趋化因子保留和呈递中的作用。在转染的 MDCK 细胞和原代人 Duffy 阳性红细胞中,CXCL12 的二聚体而非单体构建体有效地与 ACKR1 结合并内化。CXCL12 和 ACKR1 之间的这种相互作用为 CXCL12 的多种生物学功能提供了另一层调节。这些发现还提出了 ACKR1 可以结合其他二聚体趋化因子的可能性,因此可能进一步扩大 ACKR1 在趋化因子保留和呈递中的作用。在转染的 MDCK 细胞和原代人 Duffy 阳性红细胞中,CXCL12 的二聚体而非单体构建体有效地与 ACKR1 结合并内化。CXCL12 和 ACKR1 之间的这种相互作用为 CXCL12 的多种生物学功能提供了另一层调节。这些发现还提出了 ACKR1 可以结合其他二聚体趋化因子的可能性,因此可能进一步扩大 ACKR1 在趋化因子保留和呈递中的作用。

更新日期:2021-08-17
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