CXCR4
entrez
7852
canonical
uniprot
P61073
canonical
ensembl
ENSG00000121966
resolver
ensp
ENSP00000241393
resolver
ensp
ENSP00000386884
resolver
ensp
ENSP00000512429
resolver
ensp
ENSP00000512430
resolver
ensp
ENSP00000512443
resolver
enst
ENST00000466288
resolver
enst
ENST00000696137
resolver
enst
ENST00000696152
resolver
genesymbol
CXCR4
resolver
hgnc
HGNC:2561
resolver
uniprot
A0A0U3FJG0
resolver
uniprot
A0A0U3GXA9
resolver
uniprot
A0A8Q3WLL1
resolver
uniprot
B2R5N0
resolver
uniprot
O60835
resolver
uniprot
P30991
resolver
uniprot
P56438
resolver
uniprot
Q53S69
resolver
uniprot
Q9BXA0
resolver
uniprot
Q9UKN2
resolver
uniprot_entry
A0A0U3FJG0_HUMAN
resolver
uniprot_entry
A0A0U3GXA9_HUMAN
resolver
uniprot_entry
A0A8Q3WLL1_HUMAN
resolver
uniprot_entry
CXCR4_HUMAN
resolver
uniprot_sec
B2R5N0
resolver
uniprot_sec
O60835
resolver
uniprot_sec
P30991
resolver
uniprot_sec
P56438
resolver
uniprot_sec
Q53S69
resolver
uniprot_sec
Q9BXA0
resolver
uniprot_sec
Q9UKN2
resolver
amino_acid_sequence
MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVILVMGYQKKLRSMTDKYRLHLSVADLLFVITLPFWAVDAVANWYFGNFLCKAVHVIYTVNLYSSVLILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEADDRYICDRFYPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKTTVILILAFFACWLPYYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAFLGAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS
uniprot
proteins
disease_involvement
DISEASE: WHIM syndrome 1 (WHIMS1) [MIM:193670]: An autosomal dominant immunologic 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. {ECO:0000269|PubMed:12692554, ECO:0000269|PubMed:15536153}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Note=CXCR4 mutations play a role in the pathogenesis of Waldenstroem macroglobulinemia (WM) and influence disease presentation and outcome, as well as response to therapy. WM is a B-cell lymphoma characterized by accumulation of malignant lymphoplasmacytic cells in the bone marrow, lymph nodes and spleen, and hypersecretion of monoclonal immunoglobulin M (IgM). Excess IgM production results in serum hyperviscosity, tissue infiltration, and autoimmune-related pathology. {ECO:0000269|PubMed:24366360, ECO:0000269|PubMed:24553177}.
uniprot
proteins
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:10074102, PubMed:10452968, PubMed:10644702, PubMed:10825158, PubMed:18799424, PubMed:20048153, PubMed:20505072, PubMed:24912431, PubMed:28978524, PubMed:8752280, PubMed:8752281). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:16725153, PubMed:17197449, PubMed:18799424, PubMed:39093700). CXCR4 is coupled to G(i) G alpha proteins and mediates inhibition of adenylate cyclase (PubMed:17197449, PubMed:39093700). Involved in the AKT signaling cascade (PubMed:24912431). Plays a role in regulation of cell migration, e.g. during wound healing (PubMed:28978524). Also acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels (PubMed:20228059). Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Involved in hematopoiesis and in cardiac ventricular septum formation (By similarity). Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells (By similarity). Involved in cerebellar development; in the CNS, could mediate hippocampal-neuron surviva (By similarity). {ECO:0000250|UniProtKB:P70658, ECO:0000269|PubMed:10074102, ECO:0000269|PubMed:10452968, ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:16725153, ECO:0000269|PubMed:17197449, ECO:0000269|PubMed:18799424, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20228059, ECO:0000269|PubMed:20505072, ECO:0000269|PubMed:24912431, ECO:0000269|PubMed:28978524, ECO:0000269|PubMed:39093700, ECO:0000269|PubMed:8752280, ECO:0000269|PubMed:8752281}.; FUNCTION: (Microbial infection) Acts as a coreceptor (CD4 being the primary receptor) for human immunodeficiency virus-1/HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus (PubMed:10074122, PubMed:10756055, PubMed:8849450, PubMed:8929542, PubMed:9427609). {ECO:0000269|PubMed:10074122, ECO:0000269|PubMed:10756055, ECO:0000269|PubMed:8849450, ECO:0000269|PubMed:8929542, ECO:0000269|PubMed:9427609}.
uniprot
proteins
mass_dalton
39746
uniprot
proteins
mutagenesis
MUTAGEN 2..9; /note="Missing: Reduced CXCL12 binding. Abolishes signaling."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 4..20; /note="Missing: Reduced CXCL12 binding. Impaired signaling. Reduced coreceptor activity for HIV-1 isolates LAI and NDK."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 7; /note="Y->A: Reduced coreceptor activity for HIV-1 isolates LAI and NDK. Greatly reduced coreceptor activity for HIV-1 isolates LAI and NDK; when associated with A-12."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:12034737"; MUTAGEN 7; /note="Y->F: Sulfate incorporation greatly reduced; when associated with F-12 and F-21. Moderate reduction in sulfate incorporation; when associated with F-12 and A-18. No sulfate incorporation and binding SDF-1alpha greatly reduced; when associated with F-12; A-18 and F-21."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:12034737"; MUTAGEN 8; /note="T->A: No effect on sulfate incorporation; when associated with A-9 and A-13."; /evidence="ECO:0000269|PubMed:12034737"; MUTAGEN 9; /note="S->A: No effect on sulfate incorporation; when associated with A-8 and A-13."; /evidence="ECO:0000269|PubMed:12034737"; MUTAGEN 10..20; /note="Missing: Reduced CXCL12 binding. No effect on signaling."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 11; /note="N->A: Reduced molecular weight. Enhanced coreceptor activity on R5 HIV-1 isolate Envs. Slight further enhancement of coreceptor activity; when associated with A-13."; /evidence="ECO:0000269|PubMed:10756055"; MUTAGEN 12; /note="Y->A: Greatly reduced coreceptor activity for HIV-1 isolates LAI and NDK; when associated with A-7."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:12034737"; MUTAGEN 12; /note="Y->F: Sulfate incorporation greatly reduced; when associated with F-7 and F-21. Moderate reduction in sulfate incorporation; when associated with F-7 and A-18. No sulfate incorporation and binding SDF-1alpha greatly reduced; when associated with F-7; A-18 and F-21."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:12034737"; MUTAGEN 13; /note="T->A: Enhanced coreceptor activity on R5 HIV-1 isolate Envs. No effect on sulfate incorporation; when associated with A-8 and A-9."; /evidence="ECO:0000269|PubMed:10756055"; MUTAGEN 14..15; /note="EE->AA: Reduced CXCL12 binding. Reduced coreceptor activity for HIV-1 isolate NDK."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 18; /note="S->A: Sulfate incorporation greatly reduced; when associated with F-21. Moderate reduction in sulfate incorporation; when associated with F-7 and F-12. No sulfate incorporation and binding SDF-1alpha greatly reduced; when associated with F-7; F-12; and F-21."; /evidence="ECO:0000269|PubMed:12034737"; MUTAGEN 21; /note="Y->A: Reduced CXCL12 binding. Reduced coreceptor activity for HIV-1 isolates LAI and NDk."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:12034737"; MUTAGEN 21; /note="Y->F: Sulfate incorporation greatly reduced; when associated with F-7 and F-12. Sulfate incorporation greatly reduced; when associated with A-18. No sulfate incorporation and binding SDF-1alpha greatly reduced; when associated with F-7; F-12 and A-18."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:12034737"; MUTAGEN 28; /note="C->A: Reduced signaling following CXCL12-binding."; /evidence="ECO:0000269|PubMed:39093700"; MUTAGEN 97; /note="D->N: Reduced CXCL12 binding. Abolishes signaling. Markedly reduced coreceptor activity for HIV-1 isolate LAI."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 119; /note="N->D: No reduction of agonist-induced G protein activation."; /evidence="ECO:0000269|PubMed:17197449"; MUTAGEN 119; /note="N->K: Loss of agonist-induced G protein activation."; /evidence="ECO:0000269|PubMed:17197449"; MUTAGEN 119; /note="N->S: Constitutive G protein activation, with further activation induced by agonist."; /evidence="ECO:0000269|PubMed:17197449"; MUTAGEN 125; /note="L->W: Increased thermostability."; MUTAGEN 133; /note="D->N: No reduction of agonist-induced G protein activation."; /evidence="ECO:0000269|PubMed:17197449"; MUTAGEN 134; /note="R->A: Loss of agonist-induced G protein activation."; /evidence="ECO:0000269|PubMed:17197449"; MUTAGEN 135; /note="Y->A: No reduction of agonist-induced G protein activation."; /evidence="ECO:0000269|PubMed:17197449"; MUTAGEN 171; /note="D->N: Reduced coreceptor activity for HIV-1 isolate NDK."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 176; /note="N->A: Enhanced coreceptor activity on R5 HIV-1 isolate Envs; when associated with A-11."; /evidence="ECO:0000269|PubMed:10756055"; MUTAGEN 178; /note="S->A: Does not significantly affect signaling following CXCL12-binding."; /evidence="ECO:0000269|PubMed:39093700"; MUTAGEN 183; /note="R->A: Reduced coreceptor activity for several HIV-1 isolates."; /evidence="ECO:0000269|PubMed:10074102"; MUTAGEN 186; /note="C->A: Reduced signaling following CXCL12-binding."; /evidence="ECO:0000269|PubMed:39093700"; MUTAGEN 187; /note="D->A: Reduced signaling following CXCL12-binding."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:39093700"; MUTAGEN 188; /note="R->A: Reduced coreceptor activity for several HIV-1 isolates."; /evidence="ECO:0000269|PubMed:10074102"; MUTAGEN 193; /note="D->A,S,N: Greatly reduced coreceptor activity for HIV-1 isolate NDK. Reduced coreceptor activity for several other HIV-1 isolates."; /evidence="ECO:0000269|PubMed:10074102, ECO:0000269|PubMed:10825158"; MUTAGEN 193; /note="D->R: Abolishes coreceptor activity for HIV-1 isolate NDK. Reduced coreceptor activity for several other HIV-1 isolates."; /evidence="ECO:0000269|PubMed:10074102, ECO:0000269|PubMed:10825158"; MUTAGEN 240; /note="T->P: Retains ligand-binding affinity but abolishes signaling."; MUTAGEN 262; /note="D->A: Markedly reduced coreceptor activity for HIV-1 isolate LAI. Reduced signaling following CXCL12-binding."; /evidence="ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:39093700"; MUTAGEN 268; /note="E->A: Markedly reduced coreceptor activity for HIV-1 isolate NDK. Less effect for HIV-1 isolate LAI."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 281; /note="H->A: Reduced signaling following CXCL12-binding."; /evidence="ECO:0000269|PubMed:39093700"; MUTAGEN 288; /note="E->A: Reduced signaling following CXCL12-binding."; /evidence="ECO:0000269|PubMed:39093700"; MUTAGEN 288; /note="E->Q: Reduced CXCL12 binding. Impaired signaling. Reduced coreceptor activity for HIV-1 isolate LAI. Enhanced coreceptor activity for HIV-1 isolate NDK."; /evidence="ECO:0000269|PubMed:10825158"; MUTAGEN 310; /note="K->R: No effect on ubiquitination by RNF113A."; /evidence="ECO:0000269|PubMed:28978524"; MUTAGEN 324; /note="S->A: Moderate degradation. About 60% reduction in binding ITCH and no ubiquitination nor protein degradation; when associated with A-325."; /evidence="ECO:0000269|PubMed:19116316"; MUTAGEN 324; /note="S->D: Enhanced binding to ITCH. Enhanced binding to ITCH and greatly increased protein degradation; when associated with D-325."; /evidence="ECO:0000269|PubMed:19116316"; MUTAGEN 325; /note="S->A: Moderate degradation. About 60% reduction in binding ITCH and no ubiquitination nor protein degradation; when associated with A-324."; /evidence="ECO:0000269|PubMed:19116316"; MUTAGEN 325; /note="S->D: Enhanced binding to ITCH. Enhanced binding to ITCH and greatly increased protein degradation; when associated with D-324."; /evidence="ECO:0000269|PubMed:19116316"; MUTAGEN 330; /note="S->A: No effect on binding to ITCH."; /evidence="ECO:0000269|PubMed:19116316"; MUTAGEN 331; /note="K->R: Loss of ubiquitination by RNF113A."; /evidence="ECO:0000269|PubMed:28978524
uniprot
proteins
post_translational_modification
PTM: Phosphorylated on agonist stimulation (PubMed:20048153, PubMed:37209686). Phosphorylation of the P-X-P-P motif promotes association with beta-arrestin ARRB1, leading to receptor desensitization and negative regulation of G protein-coupled receptor signaling (PubMed:37209686). Phosphorylation at Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and protein degradation (PubMed:14602072, PubMed:19116316). {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:37209686}.; PTM: Ubiquitinated after ligand binding, leading to its degradation (PubMed:28978524). Ubiquitinated by ITCH at the cell membrane on agonist stimulation (PubMed:14602072, PubMed:34927784). 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, ECO:0000269|PubMed:28978524, ECO:0000269|PubMed:34927784}.; PTM: Sulfation 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}.; PTM: O- 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}.
uniprot
proteins
protein_family
G protein-coupled receptor 1 family
uniprot
proteins
pubmed
10074102
uniprot
proteins
pubmed
10074122
uniprot
proteins
pubmed
10089882
uniprot
proteins
pubmed
10452968
uniprot
proteins
pubmed
10480633
uniprot
proteins
pubmed
10644702
uniprot
proteins
pubmed
10756055
uniprot
proteins
pubmed
10825158
uniprot
proteins
pubmed
11027346
uniprot
proteins
pubmed
11276205
uniprot
proteins
pubmed
12034737
uniprot
proteins
pubmed
12692554
uniprot
proteins
pubmed
14602072
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15536153
uniprot
proteins
pubmed
15815621
uniprot
proteins
pubmed
16725153
uniprot
proteins
pubmed
17077324
uniprot
proteins
pubmed
17081983
uniprot
proteins
pubmed
17197449
uniprot
proteins
pubmed
18220336
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18799424
uniprot
proteins
pubmed
18834145
uniprot
proteins
pubmed
19116316
uniprot
proteins
pubmed
19308288
uniprot
proteins
pubmed
20048153
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20215400
uniprot
proteins
pubmed
20228059
uniprot
proteins
pubmed
20505072
uniprot
proteins
pubmed
20929726
uniprot
proteins
pubmed
21540189
uniprot
proteins
pubmed
22496149
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24366360
uniprot
proteins
pubmed
24553177
uniprot
proteins
pubmed
24912431
uniprot
proteins
pubmed
25612609
uniprot
proteins
pubmed
28978524
uniprot
proteins
pubmed
34927784
uniprot
proteins
pubmed
37209686
uniprot
proteins
pubmed
39093700
uniprot
proteins
pubmed
7505609
uniprot
proteins
pubmed
8234909
uniprot
proteins
pubmed
8276799
uniprot
proteins
pubmed
8325644
uniprot
proteins
pubmed
8329116
uniprot
proteins
pubmed
8629022
uniprot
proteins
pubmed
8752280
uniprot
proteins
pubmed
8752281
uniprot
proteins
pubmed
8849450
uniprot
proteins
pubmed
8929542
uniprot
proteins
pubmed
9427609
uniprot
proteins
pubmed
9468539
uniprot
proteins
pubmed
9599023
uniprot
proteins
pubmed
9879064
uniprot
proteins
sequence_length
352
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10452968, ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:21540189, ECO:0000305|PubMed:20929726}; Multi-pass membrane protein {ECO:0000269|PubMed:20929726}. Cell junction {ECO:0000269|PubMed:20215400}. Early endosome {ECO:0000269|PubMed:21540189}. Late endosome {ECO:0000269|PubMed:21540189}. Lysosome {ECO:0000269|PubMed:21540189}. Note=In unstimulated cells, diffuse pattern on plasma membrane (PubMed:10452968, PubMed:14602072, PubMed:21540189). On agonist stimulation, colocalizes with ITCH at the plasma membrane where it becomes ubiquitinated (PubMed:14602072). 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) (PubMed:20215400). {ECO:0000269|PubMed:10452968, ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:20215400, ECO:0000269|PubMed:21540189}.
uniprot
proteins
transmembrane_region
TRANSMEM 39..63; /note="Helical; Name=1"; /evidence="ECO:0000269|PubMed:20929726"; TRANSMEM 78..99; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:20929726"; TRANSMEM 111..130; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:20929726"; TRANSMEM 155..174; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:20929726"; TRANSMEM 196..216; /note="Helical; Name=5"; /evidence="ECO:0000269|PubMed:20929726"; TRANSMEM 242..261; /note="Helical; Name=6"; /evidence="ECO:0000269|PubMed:20929726"; TRANSMEM 283..302; /note="Helical; Name=7"; /evidence="ECO:0000269|PubMed:20929726
uniprot
proteins