ID CXCR4_MACFA Reviewed; 352 AA.
AC Q28474; Q9BDS5;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2006, sequence version 2.
DT 24-JAN-2024, entry version 112.
DE RecName: Full=C-X-C chemokine receptor type 4;
DE Short=CXC-R4;
DE Short=CXCR-4;
DE AltName: Full=Fusin {ECO:0000303|Ref.1};
DE AltName: Full=Leukocyte-derived seven transmembrane domain receptor;
DE Short=LESTR;
DE AltName: Full=Stromal cell-derived factor 1 receptor;
DE Short=SDF-1 receptor;
DE AltName: CD_antigen=CD184;
GN Name=CXCR4;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Tatsumi M., Takahashi H.;
RT "Monkey CD4 and fusin are not species barrier for HIV-1 replication.";
RL Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Wade-Evans A.M., Javan C., Jenkins A., Russell J., Sangster R.,
RA MacManus S.;
RT "Cloning, sequencing and expression of chemokine receptors, which may
RT function as SIV/SHIV co-receptors, from cynomolgus macaque PBMCs.";
RL Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces
CC a signal by increasing intracellular calcium ion levels and enhancing
CC MAPK1/MAPK3 activation. Involved in the AKT signaling cascade (By
CC similarity). Plays a role in regulation of cell migration, e.g. during
CC wound healing. Acts as a receptor for extracellular ubiquitin; leading
CC to enhanced intracellular calcium ions and reduced cellular cAMP
CC levels. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-
CC induced inflammatory response, including TNF secretion by monocytes (By
CC similarity). Involved in hematopoiesis and in cardiac ventricular
CC septum formation. Also plays an essential role in vascularization of
CC the gastrointestinal tract, probably by regulating vascular branching
CC and/or remodeling processes in endothelial cells. Involved in
CC cerebellar development. In the CNS, could mediate hippocampal-neuron
CC survival (By similarity). {ECO:0000250|UniProtKB:P61073,
CC ECO:0000250|UniProtKB:P70658}.
CC -!- SUBUNIT: Monomer. Can form homodimers. Interacts with CD164. Interacts
CC with ARRB2; the interaction is dependent on the C-terminal
CC phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3.
CC Interacts with ARR3; the interaction is dependent on the C-terminal
CC phosphorylation of CXCR4 and modulates calcium mobilization. Interacts
CC with RNF113A; the interaction, enhanced by CXCL12, promotes CXCR4
CC ubiquitination and subsequent degradation. Interacts (via the
CC cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the
CC interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and
CC leads to its degradation. Interacts with extracellular ubiquitin.
CC Interacts with DBN1; this interaction is enhanced by antigenic
CC stimulation. Following LPS binding, may form a complex with GDF5,
CC HSP90AA1 and HSPA8. {ECO:0000250|UniProtKB:P61073}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P61073};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:P61073}. Cell
CC junction {ECO:0000250}. Early endosome {ECO:0000250}. Late endosome
CC {ECO:0000250}. Lysosome {ECO:0000250}. Note=In unstimulated cells,
CC diffuse pattern on plasma membrane. On agonist stimulation, colocalizes
CC with ITCH at the plasma membrane where it becomes ubiquitinated (By
CC similarity). In the presence of antigen, distributes to the
CC immunological synapse forming at the T-cell-APC contact area, where it
CC localizes at the peripheral and distal supramolecular activation
CC cluster (SMAC) (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated on agonist stimulation. Rapidly phosphorylated on
CC serine and threonine residues in the C-terminal. Phosphorylation at
CC Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and
CC protein degradation. {ECO:0000250|UniProtKB:P61073}.
CC -!- PTM: Ubiquitinated after ligand binding, leading to its degradation.
CC Ubiquitinated by ITCH at the cell membrane on agonist stimulation. The
CC ubiquitin-dependent mechanism, endosomal sorting complex required for
CC transport (ESCRT), then targets CXCR4 for lysosomal degradation. This
CC process is dependent also on prior Ser-/Thr-phosphorylation in the C-
CC terminal of CXCR4. Also binding of ARRB1 to STAM negatively regulates
CC CXCR4 sorting to lysosomes though modulating ubiquitination of SFR5S.
CC {ECO:0000250|UniProtKB:P61073}.
CC -!- PTM: Sulfation is required for efficient binding of CXCL12/SDF-1alpha
CC and promotes its dimerization. {ECO:0000250|UniProtKB:P61073}.
CC -!- PTM: O- and N-glycosylated. N-glycosylation can mask coreceptor
CC function. The O-glycosylation chondroitin sulfate attachment does not
CC affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity.
CC {ECO:0000250|UniProtKB:P61073}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; D86579; BAA13126.1; -; mRNA.
DR EMBL; AF291672; AAK25743.1; -; mRNA.
DR PIR; G00048; G00048.
DR RefSeq; NP_001306325.1; NM_001319396.1.
DR AlphaFoldDB; Q28474; -.
DR SMR; Q28474; -.
DR STRING; 9541.ENSMFAP00000032075; -.
DR GlyCosmos; Q28474; 2 sites, No reported glycans.
DR Ensembl; ENSMFAT00000006296.2; ENSMFAP00000032075.2; ENSMFAG00000037063.2.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01050000244848; -.
DR OrthoDB; 4062414at2759; -.
DR Proteomes; UP000233100; Chromosome 12.
DR Bgee; ENSMFAG00000037063; Expressed in lymph node and 10 other cell types or tissues.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-SubCell.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0038147; F:C-X-C motif chemokine 12 receptor activity; ISS:UniProtKB.
DR GO; GO:0019955; F:cytokine binding; IEA:InterPro.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISS:UniProtKB.
DR GO; GO:0006935; P:chemotaxis; IEA:InterPro.
DR GO; GO:0038160; P:CXCL12-activated CXCR4 signaling pathway; ISS:UniProtKB.
DR CDD; cd15179; 7tmA_CXCR4; 1.
DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1.
DR InterPro; IPR022726; Chemokine_CXCR4_N_dom.
DR InterPro; IPR000355; Chemokine_rcpt.
DR InterPro; IPR001277; CXCR4/ACKR2.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR PANTHER; PTHR10489:SF594; C-X-C CHEMOKINE RECEPTOR TYPE 4; 1.
DR PANTHER; PTHR10489; CELL ADHESION MOLECULE; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR Pfam; PF12109; CXCR4_N; 1.
DR PRINTS; PR00657; CCCHEMOKINER.
DR PRINTS; PR00645; CXCCHMKINER4.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 2: Evidence at transcript level;
KW Cell junction; Cell membrane; Disulfide bond; Endosome;
KW G-protein coupled receptor; Glycoprotein; Isopeptide bond; Lysosome;
KW Membrane; Phosphoprotein; Proteoglycan; Receptor; Reference proteome;
KW Sulfation; Transducer; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..352
FT /note="C-X-C chemokine receptor type 4"
FT /id="PRO_0000069353"
FT TOPO_DOM 1..38
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 39..63
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 64..77
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 78..99
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 100..110
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 111..130
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 131..154
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 155..174
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 175..195
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 196..216
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 217..241
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 242..261
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 262..282
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 283..302
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 303..352
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT REGION 1..21
FT /note="Important for chemokine binding and signaling"
FT /evidence="ECO:0000250"
FT REGION 94..97
FT /note="Chemokine binding"
FT /evidence="ECO:0000250"
FT REGION 113..117
FT /note="Chemokine binding"
FT /evidence="ECO:0000250"
FT REGION 135..147
FT /note="Involved in dimerization; when bound to chemokine"
FT /evidence="ECO:0000250"
FT REGION 186..190
FT /note="Chemokine binding, important for signaling"
FT /evidence="ECO:0000250"
FT REGION 191..210
FT /note="Involved in dimerization"
FT /evidence="ECO:0000250"
FT REGION 266..268
FT /note="Involved in dimerization"
FT /evidence="ECO:0000250"
FT REGION 329..352
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 133..135
FT /note="Important for signaling"
FT /evidence="ECO:0000250"
FT COMPBIAS 335..352
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 171
FT /note="Chemokine"
FT /evidence="ECO:0000250"
FT SITE 288
FT /note="Chemokine"
FT /evidence="ECO:0000250"
FT MOD_RES 7
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 12
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 21
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 319
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 321
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 324
FT /note="Phosphoserine; by PKC and GRK6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 325
FT /note="Phosphoserine; by PKC and GRK6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 330
FT /note="Phosphoserine; by GRK6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 339
FT /note="Phosphoserine; by GRK6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 348
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 351
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT CARBOHYD 11
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250"
FT CARBOHYD 18
FT /note="O-linked (Xyl...) (chondroitin sulfate) serine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT DISULFID 28..274
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT DISULFID 109..186
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT CROSSLNK 331
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT CONFLICT 87
FT /note="F -> Y (in Ref. 1; BAA13126)"
FT /evidence="ECO:0000305"
FT CONFLICT 146
FT /note="K -> R (in Ref. 1; BAA13126)"
FT /evidence="ECO:0000305"
FT CONFLICT 214
FT /note="V -> A (in Ref. 2; AAK25743)"
FT /evidence="ECO:0000305"
FT CONFLICT 244
FT /note="L -> P (in Ref. 2; AAK25743)"
FT /evidence="ECO:0000305"
FT CONFLICT 291
FT /note="A -> G (in Ref. 1; BAA13126)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 352 AA; 39723 MW; F240B693D6B39C3F CRC64;
MEGISIYTSD NYTEEMGSGD YDSIKEPCFR EENAHFNRIF LPTIYSIIFL TGIVGNGLVI
LVMGYQKKLR SMTDKYRLHL SVADLLFVIT LPFWAVDAVA NWYFGNFLCK AVHVIYTVNL
YSSVLILAFI SLDRYLAIVH ATNSQKPRKL LAEKVVYVGV WIPALLLTIP DFIFASVSEA
DDRYICDRFY PNDLWVVVFQ FQHIMVGLIL PGIVILSCYC IIISKLSHSK GHQKRKALKT
TVILILAFFA CWLPYYIGIS IDSFILLEII KQGCEFENTV HKWISITEAL AFFHCCLNPI
LYAFLGAKFK TSAQHALTSV SRGSSLKILS KGKRGGHSSV STESESSSFH SS
//
