P70658 · CXCR4_MOUSE
- ProteinC-X-C chemokine receptor type 4
- GeneCxcr4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids359 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation (PubMed:8962122, PubMed:9103415, PubMed:9295051).
Involved in the AKT signaling cascade (By similarity).
Plays a role in regulation of cell migration, e.g. during wound healing. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (By similarity).
Involved in hematopoiesis and in cardiac ventricular septum formation (PubMed:9634237, PubMed:9634238, PubMed:9689100).
Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells (PubMed:9634237).
Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival (PubMed:9634238, PubMed:9689100).
Involved in the AKT signaling cascade (By similarity).
Plays a role in regulation of cell migration, e.g. during wound healing. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (By similarity).
Involved in hematopoiesis and in cardiac ventricular septum formation (PubMed:9634237, PubMed:9634238, PubMed:9689100).
Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells (PubMed:9634237).
Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival (PubMed:9634238, PubMed:9689100).
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 173 | Chemokine binding | ||||
Sequence: D | ||||||
Site | 295 | Chemokine binding | ||||
Sequence: E |
GO annotations
all annotations | all molecular function | virus receptor activity | dna binding | rna binding | cytoskeletal motor activity | catalytic activity | gtpase activity | structural molecule activity | transporter activity | cytoskeletal protein binding | lipid binding | cyclase activity | antioxidant activity | oxidoreductase activity | transferase activity | hydrolase activity | lyase activity | isomerase activity | ligase activity | protein tag activity | cargo receptor activity | histone binding | protein folding chaperone | translation regulator activity | nutrient reservoir activity | receptor ligand activity | molecular transducer activity | molecular adaptor activity | toxin activity | cell adhesion mediator activity | molecular function regulator activity | virus coreceptor activity | catalytic activity, acting on a protein | catalytic activity, acting on dna | catalytic activity, acting on rna | molecular carrier activity | transcription regulator activity | general transcription initiation factor activity | molecular sensor activity | molecular sequestering activity | atp-dependent activity | other molecular function | all biological process | mitotic cell cycle | cytokinesis | cytoplasmic translation | immune system process | muscle system process | circulatory system process | renal system process | respiratory system process | carbohydrate metabolic process | generation of precursor metabolites and energy | dna replication | dna repair | dna recombination | chromatin organization | dna-templated transcription | regulation of dna-templated transcription | trna metabolic process | protein folding | protein glycosylation | amino acid metabolic process | modified amino acid metabolic process | lipid metabolic process | vitamin metabolic process | sulfur compound metabolic process | intracellular protein transport | nucleocytoplasmic transport | autophagy | inflammatory response | mitochondrion organization | cytoskeleton organization | microtubule-based movement | peroxisome organization | lysosome organization | chromosome segregation | cell adhesion | establishment or maintenance of cell polarity | programmed cell death | photosynthesis | mrna metabolic process | snrna metabolic process | vesicle-mediated transport | reproductive process | digestive system process | signaling | cell differentiation | protein catabolic process | extracellular matrix organization | regulatory ncrna-mediated gene silencing | telomere organization | cell junction organization | wound healing | ribosome biogenesis | cilium organization | anatomical structure development | cell motility | nervous system process | endocrine process | protein maturation | transmembrane transport | nucleobase-containing small molecule metabolic process | hepaticobiliary system process | membrane organization | protein-containing complex assembly | cell wall organization or biogenesis | nitrogen cycle metabolic process | protein localization to plasma membrane | defense response to other organism | detoxification | meiotic nuclear division | mitotic nuclear division | mitochondrial gene expression | carbohydrate derivative metabolic process | other biological process | all cellular component | nuclear chromosome | extracellular region | extracellular space | cell wall | nucleus | nuclear envelope | nucleoplasm | chromosome | nucleolus | mitochondrion | lysosome | endosome | vacuole | peroxisome | endoplasmic reticulum | golgi apparatus | lipid droplet | microtubule organizing center | cytosol | ribosome | cytoskeleton | plasma membrane | cilium | plastid | thylakoid | external encapsulating structure | extracellular matrix | cytoplasmic vesicle | organelle | other cellular component | |||
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Keywords
- Molecular function
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameC-X-C chemokine receptor type 4
- Short namesCXC-R4; CXCR-4
- Alternative names
- CD Antigen Name
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionP70658
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Multi-pass membrane protein
Note: In unstimulated cells, diffuse pattern on plasma membrane. On agonist stimulation, colocalizes with ITCH at the plasma membrane where it becomes ubiquitinated (By similarity).
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) (By similarity).
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) (By similarity).
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-40 | Extracellular | ||||
Sequence: MEPISVSIYTSDNYSEEVGSGDYDSNKEPCFRDENVHFNR | ||||||
Transmembrane | 41-65 | Helical; Name=1 | ||||
Sequence: IFLPTIYFIIFLTGIVGNGLVILVM | ||||||
Topological domain | 66-79 | Cytoplasmic | ||||
Sequence: GYQKKLRSMTDKYR | ||||||
Transmembrane | 80-101 | Helical; Name=2 | ||||
Sequence: LHLSVADLLFVITLPFWAVDAM | ||||||
Topological domain | 102-112 | Extracellular | ||||
Sequence: ADWYFGKFLCK | ||||||
Transmembrane | 113-132 | Helical; Name=3 | ||||
Sequence: AVHIIYTVNLYSSVLILAFI | ||||||
Topological domain | 133-156 | Cytoplasmic | ||||
Sequence: SLDRYLAIVHATNSQRPRKLLAEK | ||||||
Transmembrane | 157-176 | Helical; Name=4 | ||||
Sequence: AVYVGVWIPALLLTIPDFIF | ||||||
Topological domain | 177-202 | Extracellular | ||||
Sequence: ADVSQGDISQGDDRYICDRLYPDSLW | ||||||
Transmembrane | 203-223 | Helical; Name=5 | ||||
Sequence: MVVFQFQHIMVGLILPGIVIL | ||||||
Topological domain | 224-248 | Cytoplasmic | ||||
Sequence: SCYCIIISKLSHSKGHQKRKALKTT | ||||||
Transmembrane | 249-268 | Helical; Name=6 | ||||
Sequence: VILILAFFACWLPYYVGISI | ||||||
Topological domain | 269-289 | Extracellular | ||||
Sequence: DSFILLGVIKQGCDFESIVHK | ||||||
Transmembrane | 290-309 | Helical; Name=7 | ||||
Sequence: WISITEALAFFHCCLNPILY | ||||||
Topological domain | 310-359 | Cytoplasmic | ||||
Sequence: AFLGAKFKSSAQHALNSMSRGSSLKILSKGKRGGHSSVSTESESSSFHSS |
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Half of the embryos die by 17.5 dpc-18.5 dpc and neonates die within a few hours. Mutants display defective vascular development, cerebellar development, B-lymphopoiesis, myelopoiesis, and cardiogenesis with defective formation of the large vessels supplying the gastrointestinal tract.
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, glycosylation, disulfide bond, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000069355 | 1-359 | C-X-C chemokine receptor type 4 | |||
Sequence: MEPISVSIYTSDNYSEEVGSGDYDSNKEPCFRDENVHFNRIFLPTIYFIIFLTGIVGNGLVILVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAMADWYFGKFLCKAVHIIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKAVYVGVWIPALLLTIPDFIFADVSQGDISQGDDRYICDRLYPDSLWMVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKTTVILILAFFACWLPYYVGISIDSFILLGVIKQGCDFESIVHKWISITEALAFFHCCLNPILYAFLGAKFKSSAQHALNSMSRGSSLKILSKGKRGGHSSVSTESESSSFHSS | ||||||
Modified residue | 9 | Sulfotyrosine | ||||
Sequence: Y | ||||||
Glycosylation | 13 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Modified residue | 14 | Sulfotyrosine | ||||
Sequence: Y | ||||||
Glycosylation | 20 | O-linked (Xyl...) (chondroitin sulfate) serine | ||||
Sequence: S | ||||||
Modified residue | 23 | Sulfotyrosine | ||||
Sequence: Y | ||||||
Disulfide bond | 30↔281 | |||||
Sequence: CFRDENVHFNRIFLPTIYFIIFLTGIVGNGLVILVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAMADWYFGKFLCKAVHIIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKAVYVGVWIPALLLTIPDFIFADVSQGDISQGDDRYICDRLYPDSLWMVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKTTVILILAFFACWLPYYVGISIDSFILLGVIKQGC | ||||||
Disulfide bond | 111↔193 | |||||
Sequence: CKAVHIIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKAVYVGVWIPALLLTIPDFIFADVSQGDISQGDDRYIC | ||||||
Modified residue | 326 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 328 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 331 | Phosphoserine; by PKC and GRK6 | ||||
Sequence: S | ||||||
Modified residue | 332 | Phosphoserine; by PKC and GRK6 | ||||
Sequence: S | ||||||
Modified residue | 337 | Phosphoserine; by GRK6 | ||||
Sequence: S | ||||||
Cross-link | 338 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 346 | Phosphoserine; by GRK6 | ||||
Sequence: S | ||||||
Modified residue | 355 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 358 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylated on agonist stimulation. Rapidly phosphorylated on serine and threonine residues in the C-terminal. Phosphorylation at Ser-331 and Ser-332 leads to recruitment of ITCH, ubiquitination and protein degradation.
Ubiquitinated after ligand binding, leading to its degradation. Ubiquitinated 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.
Sulfation is required for efficient binding of CXCL12/SDF-1alpha and promotes its dimerization.
O- and N-glycosylated. N-glycosylation can mask coreceptor function. The O-glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Lymphocytes, macrophages, neutrophils, microglial cells and astrocytes. Found in spleen, thymus, bone marrow, lymph nodes and, at lower levels in brain, small intestine, stomach and kidney. CXCR4-A is predominant in all tissues tested. During embryonic development, high levels are detected in the endothelium of developing blood vessels and in many regions of the developing brain including the olfactory epithelium, olfactory bulb, hippocampus, cerebellum and spinal cord.
Developmental stage
High expression during embryonic development does not seem to be associated with the differentiation of any particular cell type, but is widely utilized when there is a requirement for cell movement. Frequently associated with less differentiated cell types and down-regulated with subsequent differentiation. Detected in sites with hemopoietic potential: the yolk sac (7.5, 8.5 and 12.5 dpc) and fetal liver (12.5 dpc). During gastrulation, at 7.2 to 7.8 dpc, expressed in the mesoderm and the definitive endoderm. As gastrulation pattern fades (8.5 dpc), expression in the mesoderm is down-regulated, while it becomes predominant in neural ectoderm. Endodermal expression is retained in the foregut and later in a subset of foregut derivatives, including the stomach (10.5 dpc), the cystic ducts of the gall bladder and the lung epithelium (12.5 dpc). In neuronal tissue: at 10.5 and 12.5 dpc, expressed in the dorsal root ganglia, in the ventral mantle layer of the spinal cord (or basal plates), in the hindbrain. At 14.5 dpc, expression more tightly confined to the neural epithelium lining the ventricular space and to the external granular layer of the ventral rhombic lip (the developing cerebellum). Expressed in the outpocketing of the diencephalic floor at 10.5 dpc and in the developing thalamus and, to a lesser extent, the developing hypothalamus. At 14.5 dpc, restricted to the region where thalamus and hypothalamus meet. Detected in a discrete band of cells at the edge of the olfactory bulb. In the vascular system: expressed in the endothelium of numerous blood vessels, but not all, at 10.5, 11.5 and 12.5 dpc, such as vitelline/umbilical vessels, cardiac ventricular wall capillaries, facial vessels and, at 14.5 dpc, in the vasculature of the herniated gut. Expression seems to be associated with expanding vascular networks. In the heart development, expressed at 10.5 dpc in the precursor to the aortopulmonary (AP) septum. At 12.5 dpc, detected in the AP septum at the base of the outflow tract and in the atrioventricular valves. Detected in cranofacial ectoderm from 10.5 to 14.5 dpc. At 10.5 and 11.5 dpc, expressed in the Rathke pouch.
Interaction
Subunit
Monomer. Can form homodimers. Interacts with CD164. Interacts with ARRB2; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with ARR3; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates calcium mobilization. Interacts with RNF113A; the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and subsequent degradation. Interacts (via the cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and leads to its degradation. Interacts with extracellular ubiquitin. Interacts with DBN1; this interaction is enhanced by antigenic stimulation. Following LPS binding, may form a complex with GDF5, HSP90AA1 and HSPA8.
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, motif, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-23 | Important for chemokine binding and signaling | ||||
Sequence: MEPISVSIYTSDNYSEEVGSGDY | ||||||
Region | 96-99 | Chemokine binding | ||||
Sequence: WAVD | ||||||
Region | 115-119 | Chemokine binding | ||||
Sequence: HIIYT | ||||||
Motif | 135-137 | Important for signaling | ||||
Sequence: DRY | ||||||
Region | 137-149 | Involved in dimerization; when bound to chemokine | ||||
Sequence: YLAIVHATNSQRP | ||||||
Region | 193-197 | Chemokine binding, important for signaling | ||||
Sequence: CDRLY | ||||||
Region | 198-217 | Involved in dimerization | ||||
Sequence: PDSLWMVVFQFQHIMVGLIL | ||||||
Region | 273-275 | Involved in dimerization | ||||
Sequence: LLG | ||||||
Region | 335-359 | Disordered | ||||
Sequence: ILSKGKRGGHSSVSTESESSSFHSS | ||||||
Compositional bias | 342-359 | Polar residues | ||||
Sequence: GGHSSVSTESESSSFHSS |
Sequence similarities
Belongs to the G-protein coupled receptor 1 family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Protein family/group databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
P70658-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- NameCXCR4-B
- SynonymsLESTR-B
- Length359
- Mass (Da)40,426
- Last updated1997-11-01 v2
- Checksum33D1B5552A31595B
P70658-2
- NameCXCR4-A
- SynonymsLESTR-A
- Differences from canonical
- 6-7: Missing
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A0R4J0N8 | A0A0R4J0N8_MOUSE | Cxcr4 | 359 | ||
E9Q2D4 | E9Q2D4_MOUSE | Cxcr4 | 272 |
Features
Showing features for alternative sequence, sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_001891 | 6-7 | in isoform CXCR4-A | |||
Sequence: Missing | ||||||
Sequence conflict | 216 | in Ref. 4; CAA67893 and 6; BAA19187 | ||||
Sequence: I → V | ||||||
Compositional bias | 342-359 | Polar residues | ||||
Sequence: GGHSSVSTESESSSFHSS |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
U59760 EMBL· GenBank· DDBJ | AAB07725.1 EMBL· GenBank· DDBJ | mRNA | ||
U65580 EMBL· GenBank· DDBJ | AAC52953.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
D87747 EMBL· GenBank· DDBJ | BAA13451.1 EMBL· GenBank· DDBJ | mRNA | ||
Z80111 EMBL· GenBank· DDBJ | CAB02201.1 EMBL· GenBank· DDBJ | mRNA | ||
Z80112 EMBL· GenBank· DDBJ | CAB02202.1 EMBL· GenBank· DDBJ | mRNA | ||
X99581 EMBL· GenBank· DDBJ | CAA67893.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X99582 EMBL· GenBank· DDBJ | CAA67894.1 EMBL· GenBank· DDBJ | mRNA | ||
AB000803 EMBL· GenBank· DDBJ | BAA19187.1 EMBL· GenBank· DDBJ | mRNA | ||
BC031665 EMBL· GenBank· DDBJ | AAH31665.1 EMBL· GenBank· DDBJ | mRNA | ||
BC098322 EMBL· GenBank· DDBJ | AAH98322.1 EMBL· GenBank· DDBJ | mRNA |