Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Sci. Signal., 16 September 2008
Vol. 1, Issue 37, p. ra4
[DOI: 10.1126/scisignal.1160755]

RESEARCH ARTICLES

Structural Basis of CXCR4 Sulfotyrosine Recognition by the Chemokine SDF-1/CXCL12

Christopher T. Veldkamp1, Christoph Seibert2, Francis C. Peterson1, Norberto B. De la Cruz1, John C. Haugner III1, Harihar Basnet1, Thomas P. Sakmar2, and Brian F. Volkman1*

1 Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
2 Laboratory of Molecular Biology and Biochemistry, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

Abstract: Stem cell homing and breast cancer metastasis are orchestrated by the chemokine stromal cell–derived factor 1 (SDF-1) and its receptor CXCR4. Here, we report the nuclear magnetic resonance structure of a constitutively dimeric SDF-1 in complex with a CXCR4 fragment that contains three sulfotyrosine residues important for a high-affinity ligand-receptor interaction. CXCR4 bridged the SDF-1 dimer interface so that sulfotyrosines sTyr7 and sTyr12 of CXCR4 occupied positively charged clefts on opposing chemokine subunits. Dimeric SDF-1 induced intracellular Ca2+ mobilization but had no chemotactic activity; instead, it prevented native SDF-1–induced chemotaxis, suggesting that it acted as a potent partial agonist. Our work elucidates the structural basis for sulfotyrosine recognition in the chemokine-receptor interaction and suggests a strategy for CXCR4-targeted drug development.

* To whom correspondence should be addressed. E-mail: bvolkman{at}mcw.edu

Citation: C. T. Veldkamp, C. Seibert, F. C. Peterson, N. B. De la Cruz, J. C. Haugner, III, H. Basnet, T. P. Sakmar, B. F. Volkman, Structural Basis of CXCR4 Sulfotyrosine Recognition by the Chemokine SDF-1/CXCL12. Sci. Signal. 1, ra4 (2008).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Chemokine CXCL1 Dimer Is a Potent Agonist for the CXCR2 Receptor.
A. Ravindran, K. V. Sawant, J. Sarmiento, J. Navarro, and K. Rajarathnam (2013)
J. Biol. Chem. 288, 12244-12252
   Abstract »    Full Text »    PDF »
Tyrosine Sulfation of Chemokine Receptor CCR2 Enhances Interactions with Both Monomeric and Dimeric Forms of the Chemokine Monocyte Chemoattractant Protein-1 (MCP-1).
J. H. Y. Tan, J. P. Ludeman, J. Wedderburn, M. Canals, P. Hall, S. J. Butler, D. Taleski, A. Christopoulos, M. J. Hickey, R. J. Payne, et al. (2013)
J. Biol. Chem. 288, 10024-10034
   Abstract »    Full Text »    PDF »
Detecting and understanding genetic and structural features in HIV-1 B subtype V3 underlying HIV-1 co-receptor usage.
M. Chen, V. Svicher, A. Artese, G. Costa, C. Alteri, F. Ortuso, L. Parrotta, Y. Liu, C. Liu, C. F. Perno, et al. (2013)
Bioinformatics 29, 451-460
   Abstract »    Full Text »    PDF »
Heparin Oligosaccharides Inhibit Chemokine (CXC Motif) Ligand 12 (CXCL12) Cardioprotection by Binding Orthogonal to the Dimerization Interface, Promoting Oligomerization, and Competing with the Chemokine (CXC Motif) Receptor 4 (CXCR4) N Terminus.
J. J. Ziarek, C. T. Veldkamp, F. Zhang, N. J. Murray, G. A. Kartz, X. Liang, J. Su, J. E. Baker, R. J. Linhardt, and B. F. Volkman (2013)
J. Biol. Chem. 288, 737-746
   Abstract »    Full Text »    PDF »
Design and Receptor Interactions of Obligate Dimeric Mutant of Chemokine Monocyte Chemoattractant Protein-1 (MCP-1).
J. H. Y. Tan, M. Canals, J. P. Ludeman, J. Wedderburn, C. Boston, S. J. Butler, A. M. Carrick, T. R. Parody, D. Taleski, A. Christopoulos, et al. (2012)
J. Biol. Chem. 287, 14692-14702
   Abstract »    Full Text »    PDF »
Structural Determinants of Ubiquitin-CXC Chemokine Receptor 4 Interaction.
V. Saini, A. Marchese, W.-J. Tang, and M. Majetschak (2011)
J. Biol. Chem. 286, 44145-44152
   Abstract »    Full Text »    PDF »
Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways.
L. J. Drury, J. J. Ziarek, S. Gravel, C. T. Veldkamp, T. Takekoshi, S. T. Hwang, N. Heveker, B. F. Volkman, and M. B. Dwinell (2011)
PNAS 108, 17655-17660
   Abstract »    Full Text »    PDF »
The CXC Chemokine Receptor 4 Ligands Ubiquitin and Stromal Cell-derived Factor-1{alpha} Function through Distinct Receptor Interactions.
V. Saini, D. M. Staren, J. J. Ziarek, Z. N. Nashaat, E. M. Campbell, B. F. Volkman, A. Marchese, and M. Majetschak (2011)
J. Biol. Chem. 286, 33466-33477
   Abstract »    Full Text »    PDF »
CXCR7/CXCR4 Heterodimer Constitutively Recruits {beta}-Arrestin to Enhance Cell Migration.
F. M. Decaillot, M. A. Kazmi, Y. Lin, S. Ray-Saha, T. P. Sakmar, and P. Sachdev (2011)
J. Biol. Chem. 286, 32188-32197
   Abstract »    Full Text »    PDF »
Cxcl12 evolution - subfunctionalization of a ligand through altered interaction with the chemokine receptor.
B. Boldajipour, M. Doitsidou, K. Tarbashevich, C. Laguri, S. R. Yu, J. Ries, K. Dumstrei, S. Thelen, J. Dorries, E.-M. Messerschmidt, et al. (2011)
Development 138, 2909-2914
   Abstract »    Full Text »    PDF »
New G-protein-coupled receptor structures provide insights into the recognition of CXCL12 and HIV-1 gp120 by CXCR4.
C. Zhong and J. Ding (2011)
Acta Biochim Biophys Sin 43, 337-338
   Full Text »    PDF »
MIF-chemokine receptor interactions in atherogenesis are dependent on an N-loop-based 2-site binding mechanism.
S. Kraemer, H. Lue, A. Zernecke, A. Kapurniotu, E. Andreetto, R. Frank, B. Lennartz, C. Weber, and J. Bernhagen (2011)
FASEB J 25, 894-906
   Abstract »    Full Text »    PDF »
Impact of constitutional polymorphisms in VCAM1 and CD44 on CD34+ cell collection yield after administration of granulocyte colony-stimulating factor to healthy donors.
B. Martin-Antonio, M. Carmona, J. Falantes, E. Gil, A. Baez, M. Suarez, P. Marin, I. Espigado, and A. Urbano-Ispizua (2011)
Haematologica 96, 102-109
   Abstract »    Full Text »    PDF »
Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists.
B. Wu, E. Y. T. Chien, C. D. Mol, G. Fenalti, W. Liu, V. Katritch, R. Abagyan, A. Brooun, P. Wells, F. C. Bi, et al. (2010)
Science 330, 1066-1071
   Abstract »    Full Text »    PDF »
Probing the Role of CXC Motif in Chemokine CXCL8 for High Affinity Binding and Activation of CXCR1 and CXCR2 Receptors.
P. R. B. Joseph, J. M. Sarmiento, A. K. Mishra, S. T. Das, R. P. Garofalo, J. Navarro, and K. Rajarathnam (2010)
J. Biol. Chem. 285, 29262-29269
   Abstract »    Full Text »    PDF »
NMR Analysis of the Structure, Dynamics, and Unique Oligomerization Properties of the Chemokine CCL27.
A. L. Jansma, J. P. Kirkpatrick, A. R. Hsu, T. M. Handel, and D. Nietlispach (2010)
J. Biol. Chem. 285, 14424-14437
   Abstract »    Full Text »    PDF »
Structural Basis of the Interaction between Chemokine Stromal Cell-derived Factor-1/CXCL12 and Its G-protein-coupled Receptor CXCR4.
Y. Kofuku, C. Yoshiura, T. Ueda, H. Terasawa, T. Hirai, S. Tominaga, M. Hirose, Y. Maeda, H. Takahashi, Y. Terashima, et al. (2009)
J. Biol. Chem. 284, 35240-35250
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 07 October 2008.
N. R. Gough and J. F. Foley (2008)
Science Signaling 1, pc9
   Abstract »    Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882