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MGP003420

UniProt Annotations

Entry Information
Gene Namechemokine (C-X-C motif) receptor 4
Protein EntryCXCR4_HUMAN
UniProt IDP61073
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Comment=Additional isoforms seem to exist.; Name=1; IsoId=P61073-1, P30991-1; Sequence=Displayed; Name=2; Synonyms=CXCR4-LO; IsoId=P61073-2, P30991-2; Sequence=VSP_001890;
CautionWas originally (PubMed:8329116 and PubMed:8234909) thought to be a receptor for neuropeptide Y type 3 (NPY3R) (NPY3- R). {ECO:0000305}.
DiseaseWHIM syndrome (WHIM) [MIM:193670]: 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. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainThe amino-terminus is critical for ligand binding. Residues in all four extracellular regions contribute to HIV-1 coreceptor activity. {ECO:0000269|PubMed:10074122}.
FunctionReceptor 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. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes. {ECO:0000269|PubMed:10074102, ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:17197449, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20228059, ECO:0000269|PubMed:20505072, ECO:0000269|PubMed:8752280, ECO:0000269|PubMed:8752281}.
InteractionQ04900:CD164; NbExp=2; IntAct=EBI-489411, EBI-2115896; P04233:CD74; NbExp=4; IntAct=EBI-489411, EBI-2622890; P32302:CXCR5; NbExp=3; IntAct=EBI-489411, EBI-2835269; Q16643:DBN1; NbExp=5; IntAct=EBI-489411, EBI-351394; Q07266-1:Dbn1 (xeno); NbExp=3; IntAct=EBI-489411, EBI-8786792; P35579:MYH9; NbExp=5; IntAct=EBI-489411, EBI-350338;
MiscellaneousPlerixafor (AMD3100), an antagonist of CXCR4 activity, blocks HIV-1 entry, interaction with CXCL12 and subsequent CXCR4 signaling.
PtmO- and N-glycosylated. Asn-11 is the principal site of N- glycosylation. There appears to be very little or no glycosylation on Asn-176. N-glycosylation masks coreceptor function in both X4 and R5 laboratory-adapted and primary HIV-1 strains through inhibiting interaction with their Env glycoproteins. The O- glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity. {ECO:0000269|PubMed:10756055, ECO:0000269|PubMed:12034737}.
PtmPhosphorylated on agonist stimulation. Rapidly phosphorylated on serine and threonine residues in the C-terminal. Phosphorylation at Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and protein degradation. {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:20048153}.
PtmSulfation on Tyr-21 is required for efficient binding of CXCL12/SDF-1alpha and promotes its dimerization. Tyr-7 and Tyr-12 are sulfated in a sequential manner after Tyr-21 is almost fully sulfated, with the binding affinity for CXCL12/SDF-1alpha increasing with the number of sulfotyrosines present. Sulfotyrosines Tyr-7 and Tyr-12 occupy clefts on opposing CXCL12 subunits, thus bridging the CXCL12 dimer interface and promoting CXCL12 dimerization. {ECO:0000269|PubMed:10089882, ECO:0000269|PubMed:12034737, ECO:0000269|PubMed:16725153, ECO:0000269|PubMed:18834145}.
PtmUbiquitinated by ITCH at the cell membrane on agonist stimulation. The ubiquitin-dependent mechanism, endosomal sorting complex required for transport (ESCRT), then targets CXCR4 for lysosomal degradation. This process is dependent also on prior Ser-/Thr-phosphorylation in the C-terminal of CXCR4. Also binding of ARRB1 to STAM negatively regulates CXCR4 sorting to lysosomes though modulating ubiquitination of SFR5S. {ECO:0000269|PubMed:14602072}.
Sequence CautionSequence=CAA12166.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
SimilarityBelongs to the G-protein coupled receptor 1 family. {ECO:0000255|PROSITE-ProRule:PRU00521}.
Subcellular LocationCell membrane; Multi-pass membrane protein. Cell junction. Early endosome. Late endosome. Lysosome. Note=In unstimulated cells, diffuse pattern on plasma membrane. On agonist stimulation, colocalizes with ITCH at the plasma membrane where it becomes ubiquitinated. In the presence of antigen, distributes to the immunological synapse forming at the T-cell-APC contact area, where it localizes at the peripheral and distal supramolecular activation cluster (SMAC).
SubunitMonomer. Can form dimers. Interacts with CD164. Interacts with HIV-1 surface protein gp120 and Tat. Interacts with ARRB2; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with ARRC; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates calcium mobilization. Interacts (via the cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the interaction, enhanced by CXCL12, ubiquitinates CXCR4 and leads to its degradation. Interacts with extracellular ubiquitin. Interacts with human cytomegalovirus/HHV- 5 protein UL78. Interacts with DBN1; this interaction is enhanced by antigenic stimulation. Following LPS binding, may form a complex with GDF5, HSP90AA1 and HSPA8. {ECO:0000269|PubMed:10074122, ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:10756055, ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11027346, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:12034737, ECO:0000269|PubMed:16725153, ECO:0000269|PubMed:17077324, ECO:0000269|PubMed:18799424, ECO:0000269|PubMed:18834145, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20215400, ECO:0000269|PubMed:20228059, ECO:0000269|PubMed:20505072, ECO:0000269|PubMed:20929726, ECO:0000269|PubMed:22496149, ECO:0000269|PubMed:9427609}.
Tissue SpecificityExpressed in numerous tissues, such as peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex and medulla (in microglia as well as in astrocytes), brain microvascular, coronary artery and umbilical cord endothelial cells. Isoform 1 is predominant in all tissues tested. {ECO:0000269|PubMed:11276205}.
Web ResourceName=CXCR4base; Note=CXCR4 mutation db; URL="http://structure.bmc.lu.se/idbase/CXCR4base/";
Web ResourceName=SeattleSNPs; URL="http://pga.gs.washington.edu/data/cxcr4/";
Web ResourceName=Wikipedia; Note=CXC chemokine receptors entry; URL="http://en.wikipedia.org/wiki/CXC_chemokine_receptors";
Web ResourceName=Wikipedia; Note=CXCR4 entry; URL="http://en.wikipedia.org/wiki/CXCR4";
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