C-X-C chemokine receptor type 4; CXC-R4; CXCR-4; stromal cell-derived factor 1 receptor; SDF-1 receptor; fusin; leukocyte-derived seven transmembrane domain receptor; LESTR; LCR1; FB22; neuropeptide Y receptor Y3; NPYRL; HM89; CD184 (CXCR4)
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Function
- receptor for the C-X-C chemokine CXCL12/SDF-1
- role in leukocyte chemotaxis
- transduces signal by increasing the intracellular Ca+2
- role in hematopoiesis & in cardiac ventricular septum formation
- role in vascularization of the gastrointestinal tract, probably by regulating vascular branching &/or remodeling in endothelial cells
- may have role in cerebellar development
- cerebellar neuronal layering
- may have role in hippocampal-neuron survival
Structure
- monomer
- can form dimers
- sulfation on Tyr-21 is required for efficient binding of CXCL12/SDF-1alpha & promotes its dimerization
- O- & N-glycosylated
- Asn-11 is the principal site of N- glycosylation
- very little or no glycosylation on Asn-176.
- O- glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity
- amino-terminus is critical for ligand binding
- residues in all four extracellular regions contribute to HIV-1 coreceptor activity
- belongs to the G-protein coupled receptor 1 family
Compartment
Alternative splicing
named isoforms=2
Additional isoforms seem to exist
Expression
- expressed in peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex & medulla (in microglia & in astrocytes), brain microvascular, coronary artery & umbilical cord endothelial cells
- isoform 1 is predominant in all tissues tested
Pathology
- coreceptor for HIV-1 X4 isolates
- promotes Env-mediated fusion of HIV1
- N-glycosylation masks coreceptor function in both X4 & R5 laboratory-adapted & primary HIV-1 strains through inhibiting interaction with their Env glycoproteins
- interacts with HIV-1 surface protein gp120 & Tat
- primary receptor for some HIV-2 isolates
- defects in CXCR4 are a cause of WHIM syndrome
Pharmacology
- plerixaform, a CXCR4 inhibitor, investigational in treatment of NSCLC[10][11]
- mavorixafor (Xolremdi) is a selective CXCR4 antagonist approved for treatment WHIM syndrome
Notes
- originally thought to be a receptor for neuropeptide Y type 3 (NPY3R)[8][9]
More general terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/P61073.html
- ↑ CXCR4base; CXCR4 mutation db http://bioinf.uta.fi/CXCR4base/
- ↑ Wikipedia; Note: CXC chemokine receptors entry http://en.wikipedia.org/wiki/CXC_chemokine_receptors
- ↑ Wikipedia; Note: CXCR4 entry http://en.wikipedia.org/wiki/CXCR4
- ↑ SeattleSNPs http://pga.gs.washington.edu/data/cxcr4/
- ↑ Tachibana K et al The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393:591-4, 1998 PMID: https://www.ncbi.nlm.nih.gov/pubmed/9634237
- ↑ Zou YR et al Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595-9, 1998 PMID: https://www.ncbi.nlm.nih.gov/pubmed/9634238
- ↑ 8.0 8.1 Herzog H 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: https://www.ncbi.nlm.nih.gov/pubmed/8329116
- ↑ 9.0 9.1 Jazin EE et al 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: https://www.ncbi.nlm.nih.gov/pubmed/8234909
- ↑ 10.0 10.1 Burger JA, Stewart DJ. CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert Opin Investig Drugs. 2009 Apr;18(4):481-90. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19335276
- ↑ 11.0 11.1 Burger JA, Stewart DJ, Wald O, Peled A. Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev Anticancer Ther. 2011 Apr;11(4):621-30. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21504328