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反向激动纳米抗体揭示非典型趋化因子受体的组成性活性

Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies.

作者信息

Perez Almeria Claudia V, Otun Omolade, Schlimgen Roman, Lamme Thomas D, Crudden Caitrin, Youssef Noureldine, Musli Lejla, Jenjak Shawn, Bobkov Vladimir, Drube Julia, Hoffmann Carsten, Volkman Brian F, Granier Sébastien, Bechara Cherine, Siderius Marco, Heukers Raimond, Schafer Christopher T, Smit Martine J

机构信息

Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit, Amsterdam, the Netherlands.

Institut de Génomique Fonctionnelle (IGF), University of Montpellier, CNRS, INSERM, Montpellier, France.

出版信息

bioRxiv. 2024 Nov 4:2024.11.04.621790. doi: 10.1101/2024.11.04.621790.

DOI:10.1101/2024.11.04.621790
PMID:39574661
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11580867/
Abstract

Chemokine stimulation of atypical chemokine receptor 3 (ACKR3) does not activate G proteins but recruits arrestins. It is a chemokine scavenger that indirectly influences responses by restricting the availability of CXCL12, an agonist shared with the canonical receptor CXCR4. ACKR3 is upregulated in numerous disorders. Due to limited insights in chemokine-activated ACKR3 signaling, it is unclear how ACKR3 contributes to pathological phenotypes. One explanation may be that high constitutive activity of ACKR3 drives non-canonical signaling through a basal receptor state. Here we characterize the constitutive action of ACKR3 using novel inverse agonistic nanobodies to suppress basal activity. These new tools promote an inactive receptor conformation which decreased arrestin engagement and inhibited constitutive internalization. Basal, non-chemotactic, breast cancer cell motility was also suppressed, suggesting a role for ACKR3 in this process. The basal receptor activity in pathophysiology may provide a new therapeutic approach for targeting ACKR3.

摘要

趋化因子对非典型趋化因子受体3（ACKR3）的刺激不会激活G蛋白，而是募集抑制蛋白。它是一种趋化因子清除剂，通过限制与经典受体CXCR4共享的激动剂CXCL12的可用性来间接影响反应。ACKR3在多种疾病中上调。由于对趋化因子激活的ACKR3信号传导的了解有限，尚不清楚ACKR3如何导致病理表型。一种解释可能是ACKR3的高组成活性通过基础受体状态驱动非经典信号传导。在这里，我们使用新型反向激动纳米抗体抑制基础活性来表征ACKR3的组成作用。这些新工具促进了无活性的受体构象，减少了抑制蛋白的结合并抑制了组成性内化。基础的、非趋化性的乳腺癌细胞运动性也受到抑制，表明ACKR3在这个过程中发挥作用。病理生理学中的基础受体活性可能为靶向ACKR3提供一种新的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/03c4d08df169/nihpp-2024.11.04.621790v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/36e1d8d1b78d/nihpp-2024.11.04.621790v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/a39274cdae8d/nihpp-2024.11.04.621790v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/f3ea3724f953/nihpp-2024.11.04.621790v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/2709748f83d0/nihpp-2024.11.04.621790v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/c91baa686d1c/nihpp-2024.11.04.621790v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/4e29620a1cbf/nihpp-2024.11.04.621790v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/03c4d08df169/nihpp-2024.11.04.621790v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/36e1d8d1b78d/nihpp-2024.11.04.621790v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/a39274cdae8d/nihpp-2024.11.04.621790v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/f3ea3724f953/nihpp-2024.11.04.621790v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/2709748f83d0/nihpp-2024.11.04.621790v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/c91baa686d1c/nihpp-2024.11.04.621790v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/4e29620a1cbf/nihpp-2024.11.04.621790v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac2/11580867/03c4d08df169/nihpp-2024.11.04.621790v1-f0007.jpg

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本文引用的文献

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Conformational dynamics underlying atypical chemokine receptor 3 activation.非典型趋化因子受体 3 激活的构象动力学。
Proc Natl Acad Sci U S A. 2024 Jul 23;121(30):e2404000121. doi: 10.1073/pnas.2404000121. Epub 2024 Jul 15.
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Nanobody engineering: computational modelling and design for biomedical and therapeutic applications.
纳米抗体工程：用于生物医学和治疗应用的计算建模与设计
FEBS Open Bio. 2025 Feb;15(2):236-253. doi: 10.1002/2211-5463.13850. Epub 2024 Jun 19.
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Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies.细胞外 GPCR-纳米抗体的选择性和拮抗作用的结构基础。
Nat Commun. 2024 May 30;15(1):4611. doi: 10.1038/s41467-024-49000-x.
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The Role of Atypical Chemokine Receptors in Neuroinflammation and Neurodegenerative Disorders.非典型趋化因子受体在神经炎症和神经退行性疾病中的作用。
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Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer.CXCR7 对胃癌发生过程中 Hippo/YAP 轴的调控
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