2n55

From Proteopedia

(Difference between revisions)

Current revision

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

Structural highlights

2n55 is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

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^[7]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2n55"

Categories: Homo sapiens | Large Structures | Peterson FC | Volkman BF | Ziarek JJ

@@ Line 1: / Line 1: @@
 ==Structure of constitutively monomeric CXCL12 in complex with the CXCR4 N-terminus==
-<StructureSection load='2n55' size='340' side='right'caption='[[2n55]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2n55' size='340' side='right'caption='[[2n55]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2n55]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N55 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N55 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2n55]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N55 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N55 FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CXCL12, SDF1, SDF1A, SDF1B ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CXCR4 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2n55 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n55 OCA], [https://pdbe.org/2n55 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n55 RCSB], [https://www.ebi.ac.uk/pdbsum/2n55 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n55 ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[https://www.uniprot.org/uniprot/CXCR4_HUMAN CXCR4_HUMAN]] Defects in CXCR4 are a cause of WHIM syndrome (WHIM) [MIM:[https://omim.org/entry/193670 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.<ref>PMID:12692554</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/SDF1_HUMAN 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.<ref>PMID:8752281</ref> <ref>PMID:11069075</ref> <ref>PMID:11859124</ref> <ref>PMID:16107333</ref> <ref>PMID:18802065</ref> <ref>PMID:19255243</ref>  [[https://www.uniprot.org/uniprot/CXCR4_HUMAN 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.<ref>PMID:8329116</ref> <ref>PMID:8234909</ref> <ref>PMID:8629022</ref> <ref>PMID:8752280</ref> <ref>PMID:8752281</ref> <ref>PMID:10074102</ref> <ref>PMID:10644702</ref> <ref>PMID:10825158</ref> <ref>PMID:17197449</ref> <ref>PMID:20048153</ref> <ref>PMID:20228059</ref> <ref>PMID:20505072</ref>
+[https://www.uniprot.org/uniprot/SDF1_HUMAN 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.<ref>PMID:8752281</ref> <ref>PMID:11069075</ref> <ref>PMID:11859124</ref> <ref>PMID:16107333</ref> <ref>PMID:18802065</ref> <ref>PMID:19255243</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 29: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Peterson, F C]]
+[[Category: Peterson FC]]
-[[Category: Volkman, B F]]
+[[Category: Volkman BF]]
-[[Category: Ziarek, J J]]
+[[Category: Ziarek JJ]]
-[[Category: Chemokine]]
-[[Category: Cxcr4]]
-[[Category: Cxl12]]
-[[Category: Cytokine-signaling protein complex]]
-[[Category: Gpcr]]
-[[Category: Sdf1]]

2n55

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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