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Solution structure and basis for functional activity of stromal cell‐derived factor‐1; dissociation of CXCR4 activation from binding and inhibition of HIV‐1
Open accessAbstract
The three-dimensional structure of stromal cell-derived factor-1 (SDF-1) was determined by NMR spectroscopy. SDF-1 is a monomer with a disordered N-terminal region (residues 1-8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N-terminal eight residues formed an important receptor binding site; however, only Lys-1 and Pro-2 were directly involved in receptor activation. Modification to Lys-1 and/or Pro-2 resulted in loss of activity, but generated potent SDF-1 antagonists. Residues 12-17 of the loop region, which we term the RFFESH motif, unlike the N-terminal region, were well defined in the SDF-1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF-1 with its receptor. The ability of the SDF-1 analogs to block HIV-1 entry via CXCR4, which is a HIV-1 coreceptor for the virus in addition to being the receptor for SDF-1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV-1 inhibition.
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“The protein product of CCL11 resulting from differential signal peptide cleavage is predicted to retain additional amino-acid residues at its N terminus, a key region specifying binding and activity of chemokines.44”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [44]
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“It recognizes CXCL12 and cleaves between residues 2 and 3 to produce a truncated variant with a reduced affinity for, and an inability to activate, CXCR4 (38).”
BackgroundAn engineered CX3CR1 antagonist endowed with anti-inflammatory activity
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“As already mentioned, the electrostatic potential is a major factor of the chemokine binding to their receptors [133,134], we could thus establish some interesting hypothesis for the binding of CXCL-8 with DARC.”
BackgroundStructural and agonist properties of XCL2, the other member of the C-chemokine subfamily
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Nauta, A. J., Daha, M. R., Tijsma, O., van de Water, B., Tedesco, F., & Roos, A. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200203)32:3 · Cited by 147
Sequential Tyrosine Sulfation of CXCR4 by Tyrosylprotein Sulfotransferases
Seibert, C., Veldkamp, C. T., Peterson, F. C., Chait, B. T., Volkman, B. F., & Sakmar, T. P. (2008) · Biochemistry · doi:10.1021/bi800965m · Cited by 75
“NMR chemical shift assignments of SDF-1R have been described previously (22, 34, 35).”
Multiple functions of CXCL12 in a syngeneic model of breast cancer
Williams, S. A., Harata‐Lee, Y., Comerford, I., Anderson, R. L., Smyth, M. J., & McColl, S. R. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-250 · Cited by 75
Roy, I., McAllister, D. M., Gorse, E., Dixon, K. J., Piper, C., Zimmerman, N. P., Getschman, A. E., Tsai, S., Engle, D. D., Evans, D. B., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2645 · Cited by 74
“Prior reports had shown that in physiologic solutions, chemokines were capable of reversibly formingmultimeric structures, in a concentration-dependent manner (14, 24, 25).”
Relationships between glycosaminoglycan and receptor binding sites in chemokines—the CXCL12 example
Laguri, C., Arenzana‐Seisdedos, F., & Lortat‐Jacob, H. (2008) · Carbohydrate Research · doi:10.1016/j.carres.2008.01.047 · Cited by 89
Self-citationYe, J., Kohli, L. L., & Stone, M. J. (2000) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)61504-8 · Cited by 75
Yang, P., Hu, Y., & Zhou, Q. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666191113113110 · Cited by 75
Kufareva, I., Stephens, B. S., Holden, L. G., Qin, L., Zhao, C., Kawamura, T., Abagyan, R. A., & Handel, T. M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417037111 · Cited by 72
“(A–C) Nonreducing Western blot analysis of extracts from Sf9 cells coexpressing single Cys mutants of Flag-tagged CXCR4 with single Cys mutants of HA-tagged CXCL12 or its antagonist version, CXCL12(P2G) (15).”
BackgroundTian, S., Choi, W.-T., Liu, D., Pesavento, J. J., Wang, Y., An, J., Sodroski, J., & Huang, Z. (2005) · Journal of Virology · doi:10.1128/jvi.79.20.12667-12673.2005 · Cited by 72
“of CXCR4, which allows its flexible N terminus to interact with the receptor groove formed by TM domains and/or extracellular loops of CXCR4, thus triggering the receptor function (7, 14).”
BackgroundHauser, M. A., Kindinger, I., Laufer, J. M., Späte, A., Bucher, D., Vanes, S. L., Krueger, W. A., Wittmann, V., & Legler, D. F. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.2vma0915-432rr · Cited by 74
Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4
Collins, P. J., McCully, M. L., Martínez‐Muñoz, L., Santiago, C. A., Wheeldon, J., Caucheteux, S. M., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201700013r · Cited by 72
“The N terminus in CXCL14 is restricted to 2 aa (Ser-Lys), whereas in CXCL12 it is composed of 8 aa that are critical for CXCL12 activity (55).”
BackgroundResultStromal cell-derived factor-1 (SDF-1) signalling regulates human placental trophoblast cell survival
Jaleel, M. A., Tsai, A. C., Sarkar, S., Freedman, P. V., & Rubin, L. P. (2004) · Molecular Human Reproduction · doi:10.1093/molehr/gah118 · Cited by 72
“90% identity across diverse species) (Crump et al., 1997; Moepps et al., 1997) and appear to play a fundamental role in development (Nagasawa et al., 1996; Tachibana et al., 1998; Zou et al., 1998).”
BackgroundDirect Interaction between an Allosteric Agonist Pepducin and the Chemokine Receptor CXCR4
Janz, J. M., Ren, Y., Looby, R. J., Kazmi, M. A., Sachdev, P., Grunbeck, A., Haggis, L., Chinnapen, D. J. ‐., Lin, A. Y. J., Seibert, C., et al. (2011) · Journal of the American Chemical Society · doi:10.1021/ja206661w · Cited by 71
Structure Determination of Membrane Proteins by Nuclear Magnetic Resonance Spectroscopy
Opella, S. J. (2013) · Annual Review of Analytical Chemistry · doi:10.1146/annurev-anchem-062012-092631 · Cited by 71
“Previous function–structure studies showed that the intracellular loops (ICLs) of GPCRs are critical for G protein interactions (138) and suggested an activation mechanism that involves both the N-terminal residues and the extracellular loops of CXCR1 (128, 139, 140).”
BackgroundChemokine-protease interactions in cancer
Van Damme, J., Struyf, S., & Opdenakker, G. (2004) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2003.10.007 · Cited by 71
“NH2-terminal cleavage of SDF-1 by DPPIV/CD26, elastase, MMPs or cathepsin G to remove two, three, four or five amino acids, respectively, causes reduced CXCR4 affinity and impaired migratory responses of lymphocytes and CD34+ progenitor cells [64–70].”
BackgroundHuman immunodeficiency virus type-1 and chemokines: beyond competition for common cellular receptors
Stantchev, T. S., & Broder, C. C. (2001) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(00)00033-2 · Cited by 71
“Accumulated experimental results have suggested a general model for the ligand–receptor interaction where the N-loop of the chemokine makes an important initial contact with the chemokine receptor followed by a subsequent receptor activation via the chemokine’s N-terminus [49,53–56].”
BackgroundMolecular Dynamics Simulations on SDF-1α: Binding with CXCR4 Receptor
Huang, X., Shen, J., Cui, M., Shen, L., Luo, X., Ling, K., Pei, G., Jiang, H., & Chen, K. (2003) · Biophysical Journal · doi:10.1016/s0006-3495(03)74840-1 · Cited by 69
“It was also proposed (Crump et al., 1997; Loetscher et al., 1998) that the RFFESH motif (residues 12–17) is another receptor binding site and launches the initial docking of SDF-1a with its receptor.”
BackgroundResultInfluentialHow post-translational modifications influence the biological activity of chemokines
Vanheule, V., Metzemaekers, M., Janssens, R., Struyf, S., & Proost, P. (2018) · Cytokine · doi:10.1016/j.cyto.2018.02.026 · Cited by 76
Valenzuela-Fernández, A., Palanché, T., Amara, A., Magérus, A., Altmeyer, R. M., Delaunay, T., Virelizier, J., Baleux, F., Galzi, J., & Arenzana‐Seisdedos, F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100411200 · Cited by 69
Self-citationModulators of CXCR4 and CXCR7/ACKR3 Function
Adlere, I., Caspar, B., Arimont, M., Dekkers, S., Visser, K., Stuijt, J., de Graaf, C., Stocks, M. J., Kellam, B., Briddon, S. J., et al. (2019) · Molecular Pharmacology · doi:10.1124/mol.119.117663 · Cited by 68
“…CXCR4 and ACKR3 activity, which will allow the use of smaller and bioavailable peptide ligands as potential candidates for further drug discovery (Crump et al., 1997; Loetscher et al., 1998; Zhou et al., 2002; Ehrlich et al., 2013; Xu et al., 2013; Mo and Sun, 2015; Szpakowska et al., 2018).”
BackgroundMinisini, R., Tulone, C., Lüske, A., Michel, D., Mertens, T., Gierschik, P., & Moepps, B. (2003) · Journal of Virology · doi:10.1128/jvi.77.8.4489-4501.2003 · Cited by 68
“extracellular amino-terminal portion of pUS28, a region known to be critically involved in mediating ligand recognition and interaction of chemokine receptors (23), we determined whether these differences have an impact on ligand binding and/or transmembrane signaling of pUS28 encoded by the HCMV strains AD169, Toledo…”
BackgroundMarquez‐Curtis, L. A., Jalili, A., Deiteren, K., Shirvaikar, N., Lambeir, A., & Janowska‐Wieczorek, A. (2008) · Stem Cells · doi:10.1634/stemcells.2007-0725 · Cited by 68
Probing Receptor Binding Activity of Interleukin-8 Dimer Using a Disulfide Trap
Rajarathnam, K., Prado, G. N., Fernando, H., Clark‐Lewis, I., & Navarro, J. (2006) · Biochemistry · doi:10.1021/bi0605944 · Cited by 67
“Even chemokines observed as monomers in solution NMR studies at mM concentration, are observed as dimers under crystallization conditions (38,39).”
BackgroundSelf-citationSzpakowska, M., Nevins, A. M., Meyrath, M., Rhainds, D., D’huys, T., Guité‐Vinet, F., Dupuis, N., Gauthier, P., Counson, M., Kleist, A. B., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.14132 · Cited by 66
“Effects of P2G mutation on binding and activity of chemokine-derived peptides and modified CXCL11 The proline at position 2 in CXCL12 is critical for CXCR4 activation (Crump et al., 1997).”
BackgroundResultInfluentialFermas, S., Gonnet, F., Sutton, A., Charnaux, N., Mulloy, B., Du, Y., Baleux, F., & Daniel, R. (2008) · Glycobiology · doi:10.1093/glycob/cwn088 · Cited by 66
“Glycobiology vol. 18 no. 12 pp. 1054–1064, 2008 doi:10.1093/glycob/cwn088 Advance Access publication on September 16, 2008 Sulfated oligosaccharides (heparin and fucoidan) binding and dimerization of stromal cell-derived factor-1 (SDF-1/CXCL 12) are coupled as evidenced by affinity CE-MS analysis Soraya Fermas2,3, Flo…”
BackgroundInfluentialRosen, O., Sharon, M., Akabayov, S. R., & Anglister, J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606312103 · Cited by 66
Huber, B. C., Brunner, S., Segeth, A., Nathan, P., Fischer, R., Zaruba, M. M., Vallaster, M., Theiss, H. D., David, R., Gerbitz, A., et al. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr014 · Cited by 66
“977 kDa chemokine, which is secreted from endothelial cells in ischaemic tissue(16) and binds to the corresponding homing-receptor CXCR4 in its active form (1–68).(17) The interaction between SDF-1 and CXCR4, which is expressed on many circulating progenitor cells, has been shown to play an essential role in stem cell…”
BackgroundThe development and characterization of SDF1α-elastin-like-peptide nanoparticles for wound healing
Yeboah, A., Cohen, R. I., Faulknor, R., Schloss, R. S., Yarmush, M. L., & Francois Berthiaume, B. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.04.020 · Cited by 67
Bhusal, R. P., Foster, S. R., & Stone, M. J. (2019) · Protein Science · doi:10.1002/pro.3744 · Cited by 65
A Novel Peptide Antagonist of CXCR4 Derived from the N-Terminus of Viral Chemokine vMIP-II
Zhou, N., Luo, Z., Luo, J., Hall, J. W., & Huang, Z. (2000) · Biochemistry · doi:10.1021/bi992750v · Cited by 66
Rosen, O., Chill, J. H., Sharon, M., Kessler, N., Mester, B., Zolla‐Pazner, S., & Anglister, J. (2005) · Biochemistry · doi:10.1021/bi047387t · Cited by 66
CXCR4 blockade induces atherosclerosis by affecting neutrophil function
Bot, I., Daissormont, I., Zernecke, A., van Puijvelde, G. H. M., Kramp, B. K., de Jager, S. C. A., Sluimer, J. C., Manca, M., Hérias, V., Westra, M. M., et al. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.04.021 · Cited by 68
“In vitro and in vivo analysis of functionality of lentiviral CXCR4 degrakine and SDF LV.SDF1-α(P2G), LV.CXCR4deg or a shRNA targeting CXCR4 (shX4HM) without stimulation (b b 0.01 compared to LV.Empty control,”
MethodInfluentialChristopherson, K. W., Paganessi, L. A., Napier, S. C., & Porecha, N. K. (2007) · Stem Cells and Development · doi:10.1089/scd.2007.9996 · Cited by 65
“The amino terminus of chemokines interacts with the extracellular portion of chemokine receptors (19) and the removal of amino-terminal amino acids results in significant changes in functional activity (20).”
Sebastiani, S., Danelon, G., Gerber, B. O., & Uguccioni, M. (2005) · European Journal of Immunology · doi:10.1002/eji.200525800 · Cited by 65
Metadata
- Authors
- Crump, M. P., Gong, J., Loetscher, P., Rajarathnam, K., Amara, A., Arenzana‐Seisdedos, F., Virelizier, J., Baggiolini, M., Sykes, B. D., & Clark‐Lewis, I.
- Affiliations
- University of Alberta (CA)
- University of British Columbia (CA)
- University of Bern (CH)
- Institut Pasteur (FR)
- Corresponding author
- Sykes, Brian D.
- Clark‐Lewis, Ian
- Venue
- The EMBO Journal
- Published
- 1997-12-01
- Volume
- 16
- Issue
- 23
- Pages
- 6996-7007
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1170303
- OpenAlex
- W1964083898
- Cited by
- 731
- References
- 45
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 19 · 2023: 14 · 2022: 17 · 2021: 15 · 2020: 29 · 2019: 32 · 2018: 20 · 2017: 35 · 2016: 26 · 2015: 34 · 2014: 30 · 2013: 44 · 2012: 35
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- CXCL12, chemokine structure, N-terminal disordered region, receptor binding sites, CXCR4, HIV-1 coreceptor, HIV-1 entry inhibition, receptor activation, chemokine antagonists
- MeSH terms
- Amino Acid Sequence, Binding Sites, Models, Biological, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Structure-Activity Relationship, Virus Replication, HIV-1, Sequence Homology, Amino Acid, Chemokines, Anti-HIV Agents, Receptors, CXCR4, Chemokines, CXC, Nuclear Magnetic Resonance, Biomolecular, Chemokine CXCL12
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