Contents

Search

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)

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: cell membrane 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 a) promotes Env-mediated fusion of HIV1 b) N-glycosylation masks coreceptor function in both X4 & R5 laboratory-adapted & primary HIV-1 strains through inhibiting interaction with their Env glycoproteins c) 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 Note: - originally thought to be a receptor for neuropeptide Y type 3 (NPY3R) [8,9]

Interactions

molecular events

General

cluster-of-differentiation antigen; cluster designation antigen; CD antigen CXC chemokine receptor glycoprotein neuropeptide Y receptor phosphoprotein

Properties

SIZE: entity length = 352 aa MW = 40 kD COMPARTMENT: plasma membrane MOTIF: exoplasmic domain {1-39} MOTIF: N-glycosylation site {N11} Ser glycosylation site {S18} transmembrane domain {40-63} cytoplasmic loop {64-79} transmembrane domain {80-99} exoplasmic loop {100-110} MOTIF: cysteine residue {C109} MODIFICATION: cysteine residue {C186} transmembrane domain {111-132} cytoplasmic loop {133-154} MOTIF: Important for signaling {133-135} transmembrane domain {155-175} exoplasmic loop {176-200} MOTIF: N-glycosylation site {N176} cysteine residue {C186} MODIFICATION: cysteine residue {C109} transmembrane domain {201-220} cytoplasmic loop {221-240} transmembrane domain {241-261} exoplasmic loop {262-285} transmembrane domain {286-305} cytoplasmic domain {306-352} MOTIF: Ser phosphorylation site {S319} Ser phosphorylation site {S348} Ser phosphorylation site {S351}

References

  1. UniProt :accession P61073
  2. CXCR4base; CXCR4 mutation db http://bioinf.uta.fi/CXCR4base/
  3. Wikipedia; Note: CXC chemokine receptors entry http://en.wikipedia.org/wiki/CXC_chemokine_receptors
  4. Wikipedia; Note: CXCR4 entry http://en.wikipedia.org/wiki/CXCR4
  5. SeattleSNPs http://pga.gs.washington.edu/data/cxcr4/
  6. Tachibana K et al The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393:591-4, 1998 PMID: 9634237
  7. Zou YR et al Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595-9, 1998 PMID: 9634238
  8. 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: 8329116
  9. 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: 8234909
  10. Burger JA, Stewart DJ. CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert Opin Investig Drugs. 2009 Apr;18(4):481-90. Review. PMID: 19335276
  11. 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: 21504328

Databases & Figures

OMIM correlations MORBIDMAP 162643 UniProt P61073 Pfam PF00001 Entrez Gene 7852 Kegg hsa:7852 CXC ligand and receptor binding