ID CXCR4_FELCA Reviewed; 353 AA.
AC P56498; O02700; P79172;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1998, sequence version 1.
DT 27-MAR-2024, entry version 154.
DE RecName: Full=C-X-C chemokine receptor type 4;
DE Short=CXC-R4;
DE Short=CXCR-4;
DE AltName: Full=Fusin;
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 Felis catus (Cat) (Felis silvestris catus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Feliformia; Felidae; Felinae; Felis.
OX NCBI_TaxID=9685;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND CHARACTERISTICS OF FIV.
RC TISSUE=Kidney, and T-cell;
RX PubMed=9261358; DOI=10.1128/jvi.71.9.6407-6415.1997;
RA Willett B.J., Picard L., Hosie M.J., Turner J.D., Adema K., Clapham P.R.;
RT "Shared usage of the chemokine receptor CXCR4 by the feline and human
RT immunodeficiency viruses.";
RL J. Virol. 71:6407-6415(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lymphocyte;
RA Willett B.J.;
RL Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Lerner D.L., Elder J.H.;
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10470253; DOI=10.1007/s007050050503;
RA Kovacs E.M., Baxter G.D., Robinson W.F.;
RT "Feline peripheral blood mononuclear cells express message for both CXC and
RT CC type chemokines.";
RL Arch. Virol. 144:273-285(1999).
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-325 and Ser-326 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}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; U63558; AAC48852.1; -; mRNA.
DR EMBL; U92795; AAB51765.1; -; mRNA.
DR EMBL; AJ009816; CAA08839.1; -; mRNA.
DR RefSeq; NP_001009826.1; NM_001009826.1.
DR AlphaFoldDB; P56498; -.
DR SMR; P56498; -.
DR STRING; 9685.ENSFCAP00000060751; -.
DR GlyCosmos; P56498; 2 sites, No reported glycans.
DR PaxDb; 9685-ENSFCAP00000014443; -.
DR Ensembl; ENSFCAT00000015579.5; ENSFCAP00000014443.2; ENSFCAG00000015575.5.
DR GeneID; 493676; -.
DR KEGG; fca:493676; -.
DR VGNC; VGNC:61299; CXCR4.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01050000244848; -.
DR HOGENOM; CLU_009579_8_3_1; -.
DR InParanoid; P56498; -.
DR OrthoDB; 2910701at2759; -.
DR TreeFam; TF330966; -.
DR Proteomes; UP000011712; Chromosome C1.
DR Bgee; ENSFCAG00000015575; Expressed in uterus 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:0009897; C:external side of plasma membrane; IBA:GO_Central.
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:0019957; F:C-C chemokine binding; IBA:GO_Central.
DR GO; GO:0016493; F:C-C chemokine receptor activity; IBA:GO_Central.
DR GO; GO:0038147; F:C-X-C motif chemokine 12 receptor activity; ISS:UniProtKB.
DR GO; GO:0007420; P:brain development; IBA:GO_Central.
DR GO; GO:0019722; P:calcium-mediated signaling; IBA:GO_Central.
DR GO; GO:0060326; P:cell chemotaxis; IBA:GO_Central.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISS:UniProtKB.
DR GO; GO:0038160; P:CXCL12-activated CXCR4 signaling pathway; ISS:UniProtKB.
DR GO; GO:0006955; P:immune response; IBA:GO_Central.
DR GO; GO:0022008; P:neurogenesis; IBA:GO_Central.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IBA:GO_Central.
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; Host-virus interaction;
KW Isopeptide bond; Lysosome; Membrane; Phosphoprotein; Proteoglycan;
KW Receptor; Reference proteome; Sulfation; Transducer; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..353
FT /note="C-X-C chemokine receptor type 4"
FT /id="PRO_0000069351"
FT TOPO_DOM 1..39
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 40..64
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 65..78
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 79..100
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 101..111
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 112..131
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 132..155
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 156..175
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 176..196
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 197..217
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 218..242
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 243..262
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 263..283
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 284..303
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT TOPO_DOM 304..353
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT REGION 1..22
FT /note="Important for chemokine binding and signaling"
FT /evidence="ECO:0000250"
FT REGION 95..98
FT /note="Chemokine binding"
FT /evidence="ECO:0000250"
FT REGION 114..118
FT /note="Chemokine binding"
FT /evidence="ECO:0000250"
FT REGION 136..148
FT /note="Involved in dimerization; when bound to chemokine"
FT /evidence="ECO:0000250"
FT REGION 187..191
FT /note="Chemokine binding, important for signaling"
FT /evidence="ECO:0000250"
FT REGION 192..211
FT /note="Involved in dimerization"
FT /evidence="ECO:0000250"
FT REGION 267..269
FT /note="Involved in dimerization"
FT /evidence="ECO:0000250"
FT REGION 330..353
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 134..136
FT /note="Important for signaling"
FT /evidence="ECO:0000250"
FT COMPBIAS 336..353
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 172
FT /note="Chemokine binding"
FT /evidence="ECO:0000250"
FT SITE 289
FT /note="Chemokine binding"
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 22
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 320
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 322
FT /note="Phosphoserine"
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 326
FT /note="Phosphoserine; by PKC and GRK6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 331
FT /note="Phosphoserine; by GRK6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 340
FT /note="Phosphoserine; by GRK6"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 349
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT MOD_RES 352
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT CARBOHYD 11
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250"
FT CARBOHYD 19
FT /note="O-linked (Xyl...) (chondroitin sulfate) serine"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT DISULFID 29..275
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT DISULFID 110..187
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT CROSSLNK 332
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P61073"
FT CONFLICT 67
FT /note="Q -> H (in Ref. 3; AAB51765)"
FT /evidence="ECO:0000305"
FT CONFLICT 263
FT /note="D -> E (in Ref. 3; AAB51765)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 353 AA; 39936 MW; EA2BD46068A6C05B CRC64;
MDGFRIYPSD NYTEDDLGSG DYDSMKEPCF REENAHFNRI FLPTVYSIIF LTGIVGNGLV
ILVMGYQKKL RSMTDKYRLH LSVADLLFVL TLPFWAVDAV ANWYFGKFLC KAVHVIYTVN
LYSSVLILAF ISLDRYLAIV HATNSQRPRK LLAEKVVYVG VWIPALLLTI PDFIFANVRE
ADGRYICDRF YPSDSWLVVF QFQHIMVGLI LPGIVILSCY CIIISKLSHS KGYQKRKALK
TTVILILAFF ACWLPYYIGI SIDSFILLEI IKQGCEFEST VHKWISITEA LAFFHCCLNP
ILYAFLGAKF KTSAQHALTS VSRGSSLKIL SKGKRGGHSS VSTESESSSF HSS
//
