Academic Journal
Mutational analysis of the extracellular disulphide bridges of the atypical chemokine receptor ACKR3/CXCR7 uncovers multiple binding and activation modes for its chemokine and endogenous non-chemokine agonists
| العنوان: | Mutational analysis of the extracellular disulphide bridges of the atypical chemokine receptor ACKR3/CXCR7 uncovers multiple binding and activation modes for its chemokine and endogenous non-chemokine agonists |
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| المؤلفون: | Szpakowska, Martyna, Meyrath, Max Marc Roger, Reynders, Nathan, Counson, Manuel, Hanson, Julien, Steyaert, Jan, Chevigné, Andy |
| المساهمون: | Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health, Structural Biology Brussels, Vrije Universiteit Brussel, Faculty of Science, Technology and Communication, University of Luxembourg, Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, GIGA B34, University of Liège, VIB-VUB Center for Structural Biology |
| المصدر: | Biochemical Pharmacology, 153, 299-309 (2018) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2018 |
| المجموعة: | University of Liège: ORBi (Open Repository and Bibliography) |
| مصطلحات موضوعية: | ACKR3, CXCR4, chemokine receptor, CXCL12, disulfide bridge, Life sciences, Biochemistry, biophysics & molecular biology, Sciences du vivant, Biochimie, biophysique & biologie moléculaire |
| الوصف: | peer reviewed ; The atypical chemokine receptor ACKR3/CXCR7 plays crucial roles in numerous physiological processes but also in viral infection and cancer. ACKR3 shows strong propensity for activation and, unlike classical chemokine receptors, can respond to chemokines from both the CXC and CC families as well as to the endogenous peptides BAM22 and adrenomedullin. Moreover, despite belonging to the G protein coupled receptor family, its function appears to be mainly dependent on β-arrestin. ACKR3 has also been shown to continuously cycle between the plasma membrane and the endosomal compartments, suggesting a possible role as a scavenging receptor. So far, the molecular basis accounting for these atypical binding and signalling properties remains elusive. Noteworthy, ACKR3 extracellular domains bear three disulphide bridges. Two of them lie on top of the two main binding subpockets and are conserved among chemokine receptors, and one, specific to ACKR3, forms an intra-N terminus four-residue-loop of so far unknown function. Here, by mutational and functional studies, we examined the impact of the different disulphide bridges for ACKR3 folding, ligand binding and activation. We showed that, in contrast to most classical chemokine receptors, none of the extracellular disulphide bridges was essential for ACKR3 function. However, the disruption of the unique ACKR3 N-terminal loop drastically reduced the binding of CC chemokines whereas it only had a mild impact on CXC chemokine binding. Mutagenesis also uncovered that chemokine and endogenous non-chemokine ligands interact and activate ACKR3 according to distinct binding modes characterized by different transmembrane domain subpocket occupancy and N-terminal loop contribution, with BAM22 mimicking the binding mode of CC chemokine N terminus. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0006-2952 1873-2968 |
| Relation: | urn:issn:0006-2952; urn:issn:1873-2968; https://orbi.uliege.be/handle/2268/225146; info:hdl:2268/225146; info:pmid:29530506 |
| DOI: | 10.1016/j.bcp.2018.03.007 |
| الاتاحة: | https://orbi.uliege.be/handle/2268/225146 https://doi.org/10.1016/j.bcp.2018.03.007 |
| Rights: | restricted access ; http://purl.org/coar/access_right/c_16ec ; info:eu-repo/semantics/restrictedAccess |
| رقم الانضمام: | edsbas.2C96DED8 |
| قاعدة البيانات: | BASE |
| تدمد: | 00062952 18732968 |
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| DOI: | 10.1016/j.bcp.2018.03.007 |