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
Szpakowska, Martyna; Meyrath, Max Marc Roger; Reynders, Nathanet al.
2018 • In Biochemical Pharmacology, 153, p. 299-309
[en] 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.
Research Center/Unit :
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
Hanson, Julien ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Steyaert, Jan
Chevigné, Andy
Language :
English
Title :
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
Rossi, D., Zlotnik, A., The biology of chemokines and their receptors. Ann. Rev. Immunol. 18 (2000), 217–242.
Romagnani, P., Lasagni, L., Annunziato, F., Serio, M., Romagnani, S., CXC chemokines: the regulatory link between inflammation and angiogenesis. Trends Immunol. 25:4 (2004), 201–209.
Balkwill, F., Cancer and the chemokine network. Nat. Rev. Cancer 4:7 (2004), 540–550.
Bachelerie, F., Ben-Baruch, A., Burkhardt, A.M., Combadiere, C., Farber, J.M., Graham, G.J., Horuk, R., Sparre-Ulrich, A.H., Locati, M., Luster, A.D., Mantovani, A., Matsushima, K., Murphy, P.M., Nibbs, R., Nomiyama, H., Power, C.A., Proudfoot, A.E., Rosenkilde, M.M., Rot, A., Sozzani, S., Thelen, M., Yoshie, O., Zlotnik, A., International union of basic and clinical pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol. Rev. 66:1 (2014), 1–79.
Shimizu, S., Brown, M., Sengupta, R., Penfold, M.E., Meucci, O., CXCR7 protein expression in human adult brain and differentiated neurons. PLoS ONE, 6(5), 2011, e20680.
Humpert, M.L., Tzouros, M., Thelen, S., Bignon, A., Levoye, A., Arenzana-Seisdedos, F., Balabanian, K., Bachelerie, F., Langen, H., Thelen, M., Complementary methods provide evidence for the expression of CXCR7 on human B cells. Proteomics 12:12 (2012), 1938–1948.
Wang, Y., Li, G., Stanco, A., Long, J.E., Crawford, D., Potter, G.B., Pleasure, S.J., Behrens, T., Rubenstein, J.L., CXCR4 and CXCR7 have distinct functions in regulating interneuron migration. Neuron 69:1 (2011), 61–76.
Gerrits, H., van Ingen Schenau, D.S., Bakker, N.E., van Disseldorp, A.J., Strik, A., Hermens, L.S., Koenen, T.B., Krajnc-Franken, M.A., Gossen, J.A., Early postnatal lethality and cardiovascular defects in CXCR7-deficient mice. Genesis 46:5 (2008), 235–245.
Sierro, F., Biben, C., Martinez-Munoz, L., Mellado, M., Ransohoff, R.M., Li, M., Woehl, B., Leung, H., Groom, J., Batten, M., Harvey, R.P., Martinez, A.C., Mackay, C.R., Mackay, F., Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc. Natl. Acad. Sci. U.S.A. 104:37 (2007), 14759–14764.
Burns, J.M., Summers, B.C., Wang, Y., Melikian, A., Berahovich, R., Miao, Z., Penfold, M.E., Sunshine, M.J., Littman, D.R., Kuo, C.J., Wei, K., McMaster, B.E., Wright, K., Howard, M.C., Schall, T.J., A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J. Exp. Med. 203:9 (2006), 2201–2213.
Sanchez-Martin, L., Sanchez-Mateos, P., Cabanas, C., CXCR7 impact on CXCL12 biology and disease. Trends Mol. Med. 19:1 (2013), 12–22.
Grymula, K., Tarnowski, M., Wysoczynski, M., Drukala, J., Barr, F.G., Ratajczak, J., Kucia, M., Ratajczak, M.Z., Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior of human rhabdomyosarcomas. Int. J. Cancer (Journal International du Cancer) 127:11 (2010), 2554–2568.
Luker, K.E., Lewin, S.A., Mihalko, L.A., Schmidt, B.T., Winkler, J.S., Coggins, N.L., Thomas, D.G., Luker, G.D., Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene 31:45 (2012), 4750–4758.
Sun, X., Cheng, G., Hao, M., Zheng, J., Zhou, X., Zhang, J., Taichman, R.S., Pienta, K.J., Wang, J., CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 29:4 (2010), 709–722.
Wurth, R., Bajetto, A., Harrison, J.K., Barbieri, F., Florio, T., CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment. Front. Cell. Neurosci., 8, 2014, 144.
Cole, K.E., Strick, C.A., Paradis, T.J., Ogborne, K.T., Loetscher, M., Gladue, R.P., Lin, W., Boyd, J.G., Moser, B., Wood, D.E., Sahagan, B.G., Neote, K., Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J. Exp. Med. 187:12 (1998), 2009–2021.
Loetscher, M., Gerber, B., Loetscher, P., Jones, S.A., Piali, L., Clark-Lewis, I., Baggiolini, M., Moser, B., Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J. Exp. Med. 184:3 (1996), 963–969.
Balabanian, K., Lagane, B., Infantino, S., Chow, K.Y., Harriague, J., Moepps, B., Arenzana-Seisdedos, F., Thelen, M., Bachelerie, F., The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J. Biol. Chem. 280:42 (2005), 35760–35766.
Szpakowska, M., Dupuis, N., Baragli, A., Counson, M., Hanson, J., Piette, J., Chevigne, A., Human herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7. Biochem. Pharmacol., 2016.
Szpakowska, M., Chevigne, A., vCCL2/vMIP-II, the viral master KEYmokine. J. Leukocyte Biol., 2015.
Ganju, R.K., Brubaker, S.A., Meyer, J., Dutt, P., Yang, Y., Qin, S., Newman, W., Groopman, J.E., The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J. Biol. Chem. 273:36 (1998), 23169–23175.
Kalatskaya, I., Berchiche, Y.A., Gravel, S., Limberg, B.J., Rosenbaum, J.S., Heveker, N., AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol. Pharmacol. 75:5 (2009), 1240–1247.
S. Rajagopal, J. Kim, S. Ahn, S. Craig, C.M. Lam, N.P. Gerard, C. Gerard, R.J. Lefkowitz, Beta-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7, Proc Natl Acad Sci U.S.A. 107(2) 628–32.
Sun, Y., Cheng, Z., Ma, L., Pei, G., Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. J. Biol. Chem. 277:51 (2002), 49212–49219.
Naumann, U., Cameroni, E., Pruenster, M., Mahabaleshwar, H., Raz, E., Zerwes, H.G., Rot, A., Thelen, M., CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS ONE, 5(2), 2010, e9175.
Luker, K.E., Steele, J.M., Mihalko, L.A., Ray, P., Luker, G.D., Constitutive and chemokine-dependent internalization and recycling of CXCR7 in breast cancer cells to degrade chemokine ligands. Oncogene 29:32 (2010), 4599–4610.
Berahovich, R.D., Zabel, B.A., Lewen, S., Walters, M.J., Ebsworth, K., Wang, Y., Jaen, J.C., Schall, T.J., Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels. Immunology 141:1 (2014), 111–122.
Boldajipour, B., Mahabaleshwar, H., Kardash, E., Reichman-Fried, M., Blaser, H., Minina, S., Wilson, D., Xu, Q., Raz, E., Control of chemokine-guided cell migration by ligand sequestration. Cell 132:3 (2008), 463–473.
Ikeda, Y., Kumagai, H., Skach, A., Sato, M., Yanagisawa, M., Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155:6 (2013), 1323–1336.
Burg, J.S., Ingram, J.R., Venkatakrishnan, A.J., Jude, K.M., Dukkipati, A., Feinberg, E.N., Angelini, A., Waghray, D., Dror, R.O., Ploegh, H.L., Garcia, K.C., Structural biology Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science 347:6226 (2015), 1113–1117.
Zheng, Y., Qin, L., Zacarias, N.V., de Vries, H., Han, G.W., Gustavsson, M., Dabros, M., Zhao, C., Cherney, R.J., Carter, P., Stamos, D., Abagyan, R., Cherezov, V., Stevens, R.C., IJ, A.P., Heitman, L.H., Tebben, A., Kufareva, I., Handel, T.M., Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540:7633 (2016), 458–461.
Oswald, C., Rappas, M., Kean, J., Dore, A.S., Errey, J.C., Bennett, K., Deflorian, F., Christopher, J.A., Jazayeri, A., Mason, J.S., Congreve, M., Cooke, R.M., Marshall, F.H., Intracellular allosteric antagonism of the CCR9 receptor. Nature 540:7633 (2016), 462–465.
Szpakowska, M., Perez Bercoff, D., Chevigne, A., Closing the ring: a fourth extracellular loop in chemokine receptors. Sci. Signaling, 7(341), 2014, 21.
Rummel, P.C., Thiele, S., Hansen, L.S., Petersen, T.P., Sparre-Ulrich, A.H., Ulven, T., Rosenkilde, M.M., Extracellular disulfide bridges serve different purposes in two homologous chemokine receptors, CCR1 and CCR5. Mol. Pharmacol. 84:3 (2013), 335–345.
Szpakowska, M., Fievez, V., Arumugan, K., van Nuland, N., Schmit, J.C., Chevigne, A., Function, diversity and therapeutic potential of the N-terminal domain of human chemokine receptors. Biochem. Pharmacol. 84:10 (2012), 1366–1380.
Kufareva, I., Stephens, B.S., Holden, L.G., Qin, L., Zhao, C., Kawamura, T., Abagyan, R., Handel, T.M., Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: molecular modeling and experimental validation. Proc. Natl. Acad. Sci. U.S.A. 111:50 (2014), E5363–E5372.
Veldkamp, C.T., Seibert, C., Peterson, F.C., De la Cruz, N.B., Haugner, J.C. 3rd, Basnet, H., Sakmar, T.P., Volkman, B.F., Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci. Signaling, 1(37), 2008, 4.
Crump, M.P., Elisseeva, E., Gong, J., Clark-Lewis, I., Sykes, B.D., Structure/function of human herpesvirus-8 MIP-II (1–71) and the antagonist N-terminal segment (1–10). FEBS Lett. 489:2–3 (2001), 171–175.
Kleist, A.B., Getschman, A.E., Ziarek, J.J., Nevins, A.M., Gauthier, P.A., Chevigne, A., Szpakowska, M., Volkman, B.F., New paradigms in chemokine receptor signal transduction: moving beyond the two-site model. Biochem. Pharmacol., 2016.
Chevigne, A., Fievez, V., Schmit, J.C., Deroo, S., Engineering and screening the N-terminus of chemokines for drug discovery. Biochem. Pharmacol. 82:10 (2011), 1438–1456.
Crump, M.P., Gong, J.H., Loetscher, P., Rajarathnam, K., Amara, A., Arenzana-Seisdedos, F., Virelizier, J.L., Baggiolini, M., Sykes, B.D., Clark-Lewis, I., Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J. 16:23 (1997), 6996–7007.
Chevigne, A., Fievez, V., Szpakowska, M., Fischer, A., Counson, M., Plesseria, J.M., Schmit, J.C., Deroo, S., Neutralising properties of peptides derived from CXCR4 extracellular loops towards CXCL12 binding and HIV-1 infection. Biochim. Biophys. Acta 1843:5 (2014), 1031–1041.
Surgand, J.S., Rodrigo, J., Kellenberger, E., Rognan, D., A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Proteins 62:2 (2006), 509–538.
Scholten, D.J., Canals, M., Maussang, D., Roumen, L., Smit, M.J., Wijtmans, M., de Graaf, C., Vischer, H.F., Leurs, R., Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165:6 (2012), 1617–1643.
Szpakowska, M., Nevins, A., Meyrath, M., Rhainds, D., D'huys, T., Guité-Vinet, F., Dupuis, N., Gauthier, P.-A., Counson, M., Kleist, A., St-Onge, G., Hanson, J., Schols, D., Volkman, B., Heveker, N., Chevigné A., Different contribution of chemokine N-terminal features attest a different ligand binding mode and a bias towards activation of the atypical chemokine receptor ACKR3/CXCR7 compared to CXCR4 and CXCR3. Br. J. Pharmacol., 2017.
Benredjem, B., Girard, M., Rhainds, D., St-Onge, G., Heveker, N., Mutational analysis of atypical chemokine receptor 3 (ACKR3/CXCR7) interaction with its chemokine ligands CXCL11 and CXCL12. J. Biol. Chem. 292:1 (2017), 31–42.
Dupuis, N., Laschet, C., Franssen, D., Szpakowska, M., Gilissen, J., Geubelle, P., Soni, A., Parent, A.S., Pirotte, B., Chevigne, A., Twizere, J.C., Hanson, J., Activation of the orphan G protein-coupled receptor GPR27 by surrogate ligands promotes beta-arrestin 2 recruitment. Mol. Pharmacol. 91:6 (2017), 595–608.
Dixon, A.S., Schwinn, M.K., Hall, M.P., Zimmerman, K., Otto, P., Lubben, T.H., Butler, B.L., Binkowski, B.F., Machleidt, T., Kirkland, T.A., Wood, M.G., Eggers, C.T., Encell, L.P., Wood, K.V., NanoLuc complementation reporter optimized for accurate measurement of protein interactions in Cells. ACS Chem. Biol. 11:2 (2016), 400–408.
Infantino, S., Moepps, B., Thelen, M., Expression and regulation of the orphan receptor RDC1 and its putative ligand in human dendritic and B cells. J. Immunol. 176:4 (2006), 2197–2207.
Chabot, D.J., Zhang, P.F., Quinnan, G.V., Broder, C.C., Mutagenesis of CXCR4 identifies important domains for human immunodeficiency virus type 1 X4 isolate envelope-mediated membrane fusion and virus entry and reveals cryptic coreceptor activity for R5 isolates. J. Virol. 73:8 (1999), 6598–6609.
Ai, L.S., Liao, F., Mutating the four extracellular cysteines in the chemokine receptor CCR6 reveals their differing roles in receptor trafficking, ligand binding, and signaling. Biochemistry 41:26 (2002), 8332–8341.
Limatola, C., Di Bartolomeo, S., Catalano, M., Trettel, F., Fucile, S., Castellani, L., Eusebi, F., Cysteine residues are critical for chemokine receptor CXCR2 functional properties. Exp. Cell Res. 307:1 (2005), 65–75.
Ziarek, J.J., Kleist, A.B., London, N., Raveh, B., Montpas, N., Bonneterre, J., St-Onge, G., DiCosmo-Ponticello, C.J., Koplinski, C.A., Roy, I., Stephens, B., Thelen, S., Veldkamp, C.T., Coffman, F.D., Cohen, M.C., Dwinell, M.B., Thelen, M., Peterson, F.C., Heveker, N., Volkman, B.F., Structural basis for chemokine recognition by a G protein-coupled receptor and implications for receptor activation. Sci. Signaling, 10(471), 2017.
