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Protein

Atypical chemokine receptor 3

Gene

ACKR3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines CXCL11 and CXCL12/SDF1. Chemokine binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization and activation of MAPK signaling pathway. Required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness. In glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis. Promotes cell growth and survival. Not involved in cell migration, adhesion or proliferation of normal hematopoietic progenitors but activated by CXCL11 in malignant hemapoietic cells, leading to phosphorylation of ERK1/2 (MAPK3/MAPK1) and enhanced cell adhesion and migration. Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12. Required for heart valve development. Acts as coreceptor with CXCR4 for a restricted number of HIV isolates.12 Publications

Caution

Was originally thought to be the receptor for VIP.1 Publication

GO - Molecular functioni

  • coreceptor activity Source: InterPro
  • C-X-C chemokine binding Source: UniProtKB
  • C-X-C chemokine receptor activity Source: BHF-UCL
  • scavenger receptor activity Source: UniProtKB

GO - Biological processi

  • angiogenesis Source: InterPro
  • cell adhesion Source: UniProtKB-KW
  • chemokine-mediated signaling pathway Source: BHF-UCL
  • chemotaxis Source: InterPro
  • G-protein coupled receptor signaling pathway Source: Reactome
  • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage Source: BHF-UCL
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of mesenchymal stem cell migration Source: Ensembl
  • receptor internalization Source: UniProtKB
  • vasculogenesis Source: InterPro
  • viral process Source: UniProtKB-KW

Keywordsi

Molecular functionDevelopmental protein, G-protein coupled receptor, Receptor, Transducer
Biological processCell adhesion, Host-virus interaction

Enzyme and pathway databases

ReactomeiR-HSA-380108 Chemokine receptors bind chemokines
R-HSA-418594 G alpha (i) signalling events
SignaLinkiP25106
SIGNORiP25106

Names & Taxonomyi

Protein namesi
Recommended name:
Atypical chemokine receptor 3
Alternative name(s):
C-X-C chemokine receptor type 7
Short name:
CXC-R7
Short name:
CXCR-7
Chemokine orphan receptor 1
G-protein coupled receptor 159
G-protein coupled receptor RDC1 homolog
Short name:
RDC-1
Gene namesi
Name:ACKR3
Synonyms:CMKOR1, CXCR7, GPR159, RDC1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

EuPathDBiHostDB:ENSG00000144476.5
HGNCiHGNC:23692 ACKR3
MIMi610376 gene
neXtProtiNX_P25106

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 40ExtracellularSequence analysisAdd BLAST40
Transmembranei41 – 61Helical; Name=1Sequence analysisAdd BLAST21
Topological domaini62 – 81CytoplasmicSequence analysisAdd BLAST20
Transmembranei82 – 102Helical; Name=2Sequence analysisAdd BLAST21
Topological domaini103 – 118ExtracellularSequence analysisAdd BLAST16
Transmembranei119 – 139Helical; Name=3Sequence analysisAdd BLAST21
Topological domaini140 – 162CytoplasmicSequence analysisAdd BLAST23
Transmembranei163 – 183Helical; Name=4Sequence analysisAdd BLAST21
Topological domaini184 – 213ExtracellularSequence analysisAdd BLAST30
Transmembranei214 – 234Helical; Name=5Sequence analysisAdd BLAST21
Topological domaini235 – 252CytoplasmicSequence analysisAdd BLAST18
Transmembranei253 – 273Helical; Name=6Sequence analysisAdd BLAST21
Topological domaini274 – 296ExtracellularSequence analysisAdd BLAST23
Transmembranei297 – 319Helical; Name=7Sequence analysisAdd BLAST23
Topological domaini320 – 362CytoplasmicSequence analysisAdd BLAST43

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Endosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi145S → A: Does not result in CXCL12-inducible chemotaxis, calcium mobilization or ERK activation, and has no effect on CXCR7-mediated CXCL12 degradation; when associated with V-147. 1 Publication1
Mutagenesisi147T → V: Does not result in CXCL12-inducible chemotaxis, calcium mobilization or ERK activation, and has no effect on CXCR7-mediated CXCL12 degradation; when associated with A-145. 1 Publication1

Organism-specific databases

DisGeNETi57007
OpenTargetsiENSG00000144476
PharmGKBiPA162383053

Chemistry databases

ChEMBLiCHEMBL2010631
GuidetoPHARMACOLOGYi80

Polymorphism and mutation databases

BioMutaiCXCR7
DMDMi115502380

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000701011 – 362Atypical chemokine receptor 3Add BLAST362

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi13N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi22N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi39N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi117 ↔ 196PROSITE-ProRule annotation
Modified residuei347PhosphoserineBy similarity1
Modified residuei350PhosphoserineBy similarity1
Modified residuei355PhosphoserineBy similarity1

Post-translational modificationi

The Ser/Thr residues in the C-terminal cytoplasmic tail may be phosphorylated.
Ubiquitinated at the Lys residues in its C-terminal cytoplasmic tail and is essential for correct trafficking from and to the cell membrane. Deubiquitinated by CXCL12-stimulation in a reversible manner.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP25106
PaxDbiP25106
PeptideAtlasiP25106
PRIDEiP25106

PTM databases

iPTMnetiP25106
PhosphoSitePlusiP25106

Expressioni

Tissue specificityi

Expressed in monocytes, basophils, B-cells, umbilical vein endothelial cells (HUVEC) and B-lymphoblastoid cells. Lower expression detected in CD4+ T-lymphocytes and natural killer cells. In the brain, detected in endothelial cells and capillaries, and in mature neurons of the frontal cortex and hippocampus. Expressed in tubular formation in the kidney. Highly expressed in astroglial tumor endothelial, microglial and glioma cells. Expressed at low levels in normal CD34+ progenitor cells, but at very high levels in several myeloid malignant cell lines. Expressed in breast carcinomas but not in normal breast tissue (at protein level).6 Publications

Inductioni

Up-regulated during cell differentiation in glioma cells.1 Publication

Gene expression databases

BgeeiENSG00000144476
CleanExiHS_CXCR7
ExpressionAtlasiP25106 baseline and differential
GenevisibleiP25106 HS

Organism-specific databases

HPAiHPA032003
HPA049718

Interactioni

Subunit structurei

Homodimer. Can form heterodimers with CXCR4; heterodimerization may regulate CXCR4 signaling activity. Interacts with ARRB1 and ARRB2.4 Publications

GO - Molecular functioni

  • C-X-C chemokine binding Source: UniProtKB

Protein-protein interaction databases

BioGridi12132112 interactors.
IntActiP25106 15 interactors.
STRINGi9606.ENSP00000272928

Chemistry databases

BindingDBiP25106

Structurei

3D structure databases

ProteinModelPortaliP25106
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni324 – 362C-terminal cytoplasmic tailAdd BLAST39

Domaini

The C-terminal cytoplasmic tail, plays a key role in: correct trafficking to the cell membrane, recruitment of beta-arrestin, ubiquitination, and in chemokine scavenging and signaling functions. The Ser/Thr residues and the Lys residues in the C-terminal cytoplasmic tail are essential for beta-arrestin recruitment and ubiquitination respectively.

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family. Atypical chemokine receptor subfamily.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3656 Eukaryota
ENOG410XRW9 LUCA
GeneTreeiENSGT00760000119055
HOGENOMiHOG000261660
HOVERGENiHBG106832
InParanoidiP25106
KOiK04304
OMAiYIPFTCQ
OrthoDBiEOG091G091W
PhylomeDBiP25106
TreeFamiTF333489

Family and domain databases

CDDicd14987 7tmA_ACKR3_CXCR7, 1 hit
InterProiView protein in InterPro
IPR001416 ACKR3
IPR000276 GPCR_Rhodpsn
IPR017452 GPCR_Rhodpsn_7TM
PANTHERiPTHR44720 PTHR44720, 1 hit
PfamiView protein in Pfam
PF00001 7tm_1, 1 hit
PRINTSiPR00237 GPCRRHODOPSN
PR00646 RDC1ORPHANR
PROSITEiView protein in PROSITE
PS00237 G_PROTEIN_RECEP_F1_1, 1 hit
PS50262 G_PROTEIN_RECEP_F1_2, 1 hit

Sequencei

Sequence statusi: Complete.

P25106-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDLHLFDYSE PGNFSDISWP CNSSDCIVVD TVMCPNMPNK SVLLYTLSFI
60 70 80 90 100
YIFIFVIGMI ANSVVVWVNI QAKTTGYDTH CYILNLAIAD LWVVLTIPVW
110 120 130 140 150
VVSLVQHNQW PMGELTCKVT HLIFSINLFG SIFFLTCMSV DRYLSITYFT
160 170 180 190 200
NTPSSRKKMV RRVVCILVWL LAFCVSLPDT YYLKTVTSAS NNETYCRSFY
210 220 230 240 250
PEHSIKEWLI GMELVSVVLG FAVPFSIIAV FYFLLARAIS ASSDQEKHSS
260 270 280 290 300
RKIIFSYVVV FLVCWLPYHV AVLLDIFSIL HYIPFTCRLE HALFTALHVT
310 320 330 340 350
QCLSLVHCCV NPVLYSFINR NYRYELMKAF IFKYSAKTGL TKLIDASRVS
360
ETEYSALEQS TK
Length:362
Mass (Da):41,493
Last modified:October 3, 2006 - v3
Checksum:iA863EC1AFB5B158B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti9S → A in AAA62370 (PubMed:1675791).Curated1
Sequence conflicti130G → S in AAA62370 (PubMed:1675791).Curated1
Sequence conflicti130G → S in AAB16913 (Ref. 2) Curated1
Sequence conflicti130G → S in AAB94130 (Ref. 3) Curated1
Sequence conflicti131S → G in AAA62370 (PubMed:1675791).Curated1
Sequence conflicti228I → V in AAH36661 (PubMed:15489334).Curated1
Sequence conflicti360 – 361ST → NA in AAA62370 (PubMed:1675791).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_027477219L → W. Corresponds to variant dbSNP:rs10183641Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M64749 mRNA Translation: AAA62370.1
U73141 Genomic DNA Translation: AAB18130.1
U67784 mRNA Translation: AAB16913.1
AF030297 mRNA Translation: AAB94130.1
DQ822477 mRNA Translation: ABH01258.1
AK291659 mRNA Translation: BAF84348.1
AC079611 Genomic DNA Translation: AAX93086.1
CH471063 Genomic DNA Translation: EAW71092.1
BC036661 mRNA Translation: AAH36661.1
CCDSiCCDS2516.1
PIRiA39714
RefSeqiNP_064707.1, NM_020311.2
XP_005246154.1, XM_005246097.2
XP_005246155.1, XM_005246098.3
XP_016860005.1, XM_017004516.1
UniGeneiHs.471751

Genome annotation databases

EnsembliENST00000272928; ENSP00000272928; ENSG00000144476
GeneIDi57007
KEGGihsa:57007
UCSCiuc002vwd.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiACKR3_HUMAN
AccessioniPrimary (citable) accession number: P25106
Secondary accession number(s): A8K6J4
, Q53RV4, Q8NE10, Q92938, Q92986
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 1, 1992
Last sequence update: October 3, 2006
Last modified: April 25, 2018
This is version 178 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome