2n55

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Structure of constitutively monomeric CXCL12 in complex with the CXCR4 N-terminusStructure of constitutively monomeric CXCL12 in complex with the CXCR4 N-terminus

Structural highlights

2n55 is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:CXCL12, SDF1, SDF1A, SDF1B (HUMAN), CXCR4 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CXCR4_HUMAN] Defects in CXCR4 are a cause of WHIM syndrome (WHIM) [MIM:193670]; also known as warts, hypogammaglobulinemia, infections and myelokathexis. WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis.[1]

Function

[SDF1_HUMAN] Chemoattractant active on T-lymphocytes, monocytes, but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. Also binds to another C-X-C chemokine receptor CXCR7, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and CXCR7, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of CXCR7 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation.[2] [3] [4] [5] [6] [7] [CXCR4_HUMAN] Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]

Publication Abstract from PubMed

Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family. We demonstrated that a constitutively monomeric CXCL12 variant reproduced the G protein-dependent and beta-arrestin-dependent responses that are associated with normal CXCR4 signaling and lead to cell migration. In addition, monomeric CXCL12 made specific contacts with CXCR4 that are not present in the structure of the receptor in complex with a dimeric form of CXCL12, a biased agonist that stimulates only G protein-dependent signaling. We produced an experimentally validated model of an agonist-bound chemokine receptor that merged a nuclear magnetic resonance-based structure of monomeric CXCL12 bound to the amino terminus of CXCR4 with a crystal structure of the transmembrane domains of CXCR4. The large CXCL12:CXCR4 protein-protein interface revealed by this structure identified previously uncharacterized functional interactions that fall outside of the classical "two-site model" for chemokine-receptor recognition. Our model suggests a mechanistic hypothesis for how interactions on the extracellular face of the receptor may stimulate the conformational changes required for chemokine receptor-mediated signal transduction.

Structural basis for chemokine recognition by a G protein-coupled receptor and implications for receptor activation.,Ziarek JJ, Kleist AB, London N, Raveh B, Montpas N, Bonneterre J, St-Onge G, DiCosmo-Ponticello CJ, Koplinski CA, Roy I, Stephens B, Thelen S, Veldkamp CT, Coffman FD, Cohen MC, Dwinell MB, Thelen M, Peterson FC, Heveker N, Volkman BF Sci Signal. 2017 Mar 21;10(471). pii: eaah5756. doi: 10.1126/scisignal.aah5756. PMID:28325822[20]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, Klotman ME, Diaz GA. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet. 2003 May;34(1):70-4. PMID:12692554 doi:10.1038/ng1149
  2. ↑ Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996 Aug 29;382(6594):833-5. PMID:8752281 doi:10.1038/382833a0
  3. ↑ Moepps B, Braun M, Knopfle K, Dillinger K, Knochel W, Gierschik P. Characterization of a Xenopus laevis CXC chemokine receptor 4: implications for hematopoietic cell development in the vertebrate embryo. Eur J Immunol. 2000 Oct;30(10):2924-34. PMID:11069075
  4. ↑ Braun M, Wunderlin M, Spieth K, Knochel W, Gierschik P, Moepps B. Xenopus laevis Stromal cell-derived factor 1: conservation of structure and function during vertebrate development. J Immunol. 2002 Mar 1;168(5):2340-7. PMID:11859124
  5. ↑ Balabanian K, Lagane B, Infantino S, Chow KY, 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. 2005 Oct 21;280(42):35760-6. Epub 2005 Aug 17. PMID:16107333 doi:M508234200
  6. ↑ Malik M, Chen YY, Kienzle MF, Tomkowicz BE, Collman RG, Ptasznik A. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase. J Immunol. 2008 Oct 1;181(7):4632-7. PMID:18802065
  7. ↑ Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N. AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol. 2009 May;75(5):1240-7. doi: 10.1124/mol.108.053389. Epub 2009 Mar , 2. PMID:19255243 doi:10.1124/mol.108.053389
  8. ↑ Herzog H, Hort YJ, Shine J, Selbie LA. Molecular cloning, characterization, and localization of the human homolog to the reported bovine NPY Y3 receptor: lack of NPY binding and activation. DNA Cell Biol. 1993 Jul-Aug;12(6):465-71. PMID:8329116
  9. ↑ Jazin EE, Yoo H, Blomqvist AG, Yee F, Weng G, Walker MW, Salon J, Larhammar D, Wahlestedt C. A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human homologue, confers neither NPY binding sites nor NPY responsiveness on transfected cells. Regul Pept. 1993 Sep 22;47(3):247-58. PMID:8234909
  10. ↑ Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872-7. PMID:8629022
  11. ↑ Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996 Aug 29;382(6594):829-33. PMID:8752280 doi:10.1038/382829a0
  12. ↑ Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996 Aug 29;382(6594):833-5. PMID:8752281 doi:10.1038/382833a0
  13. ↑ Brelot A, Heveker N, Adema K, Hosie MJ, Willett B, Alizon M. Effect of mutations in the second extracellular loop of CXCR4 on its utilization by human and feline immunodeficiency viruses. J Virol. 1999 Apr;73(4):2576-86. PMID:10074102
  14. ↑ Cheng ZJ, Zhao J, Sun Y, Hu W, Wu YL, Cen B, Wu GX, Pei G. beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta-arrestin and CXCR4. J Biol Chem. 2000 Jan 28;275(4):2479-85. PMID:10644702
  15. ↑ Brelot A, Heveker N, Montes M, Alizon M. Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. J Biol Chem. 2000 Aug 4;275(31):23736-44. PMID:10825158 doi:10.1074/jbc.M000776200
  16. ↑ Berchiche YA, Chow KY, Lagane B, Leduc M, Percherancier Y, Fujii N, Tamamura H, Bachelerie F, Heveker N. Direct assessment of CXCR4 mutant conformations reveals complex link between receptor structure and G(alpha)(i) activation. J Biol Chem. 2007 Feb 23;282(8):5111-5. Epub 2006 Dec 29. PMID:17197449 doi:10.1074/jbc.C600270200
  17. ↑ Busillo JM, Armando S, Sengupta R, Meucci O, Bouvier M, Benovic JL. Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling. J Biol Chem. 2010 Mar 5;285(10):7805-17. doi: 10.1074/jbc.M109.091173. Epub 2010 , Jan 4. PMID:20048153 doi:10.1074/jbc.M109.091173
  18. ↑ Saini V, Marchese A, Majetschak M. CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin. J Biol Chem. 2010 May 14;285(20):15566-76. doi: 10.1074/jbc.M110.103408. Epub, 2010 Mar 12. PMID:20228059 doi:10.1074/jbc.M110.103408
  19. ↑ Malik R, Marchese A. Arrestin-2 interacts with the endosomal sorting complex required for transport machinery to modulate endosomal sorting of CXCR4. Mol Biol Cell. 2010 Jul 15;21(14):2529-41. doi: 10.1091/mbc.E10-02-0169. Epub, 2010 May 26. PMID:20505072 doi:10.1091/mbc.E10-02-0169
  20. ↑ Ziarek JJ, Kleist AB, London N, Raveh B, Montpas N, Bonneterre J, St-Onge G, DiCosmo-Ponticello CJ, Koplinski CA, Roy I, Stephens B, Thelen S, Veldkamp CT, Coffman FD, Cohen MC, Dwinell MB, Thelen M, Peterson FC, Heveker N, Volkman BF. Structural basis for chemokine recognition by a G protein-coupled receptor and implications for receptor activation. Sci Signal. 2017 Mar 21;10(471). pii: eaah5756. doi: 10.1126/scisignal.aah5756. PMID:28325822 doi:http://dx.doi.org/10.1126/scisignal.aah5756
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