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Protein

Atypical chemokine receptor 3

Gene

ACKR3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

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
  • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage Source: BHF-UCL
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • receptor internalization Source: UniProtKB
  • vasculogenesis Source: InterPro
  • viral process Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, G-protein coupled receptor, Receptor, Transducer

Keywords - Biological processi

Cell adhesion, Host-virus interaction

Enzyme and pathway databases

BioCyciZFISH:ENSG00000144476-MONOMER.
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

HGNCiHGNC:23692. ACKR3.

Subcellular locationi

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

GO - Cellular componenti

  • cell surface Source: UniProtKB
  • clathrin-coated pit Source: UniProtKB
  • early endosome Source: UniProtKB-SubCell
  • endosome Source: UniProtKB
  • integral component of membrane Source: UniProtKB-KW
  • intracellular membrane-bounded organelle Source: HPA
  • perinuclear region of cytoplasm Source: UniProtKB-SubCell
  • plasma membrane Source: UniProtKB
  • recycling endosome Source: UniProtKB-SubCell
Complete GO annotation...

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...)Sequence analysis1
Glycosylationi22N-linked (GlcNAc...)Sequence analysis1
Glycosylationi39N-linked (GlcNAc...)Sequence 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

BioGridi121321. 11 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

InterProiIPR001416. ACKR3.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view]
PANTHERiPTHR10489:SF682. PTHR10489:SF682. 1 hit.
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR00646. RDC1ORPHANR.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

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 rs10183641dbSNPEnsembl.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

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology
Wikipedia

CXC chemokine receptors entry

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.

3D structure databases

ProteinModelPortaliP25106.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121321. 11 interactors.
IntActiP25106. 15 interactors.
STRINGi9606.ENSP00000272928.

Chemistry databases

BindingDBiP25106.
ChEMBLiCHEMBL2010631.
GuidetoPHARMACOLOGYi80.

Protein family/group databases

GPCRDBiSearch...

PTM databases

iPTMnetiP25106.
PhosphoSitePlusiP25106.

Polymorphism and mutation databases

BioMutaiCXCR7.
DMDMi115502380.

Proteomic databases

MaxQBiP25106.
PaxDbiP25106.
PeptideAtlasiP25106.
PRIDEiP25106.

Protocols and materials databases

DNASUi57007.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi57007.
DisGeNETi57007.
GeneCardsiACKR3.
HGNCiHGNC:23692. ACKR3.
HPAiHPA032003.
HPA049718.
MIMi610376. gene.
neXtProtiNX_P25106.
OpenTargetsiENSG00000144476.
PharmGKBiPA162383053.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

BioCyciZFISH:ENSG00000144476-MONOMER.
ReactomeiR-HSA-380108. Chemokine receptors bind chemokines.
R-HSA-418594. G alpha (i) signalling events.
SignaLinkiP25106.
SIGNORiP25106.

Miscellaneous databases

ChiTaRSiACKR3. human.
GeneWikiiCXCR7.
GenomeRNAii57007.
PROiP25106.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000144476.
CleanExiHS_CXCR7.
ExpressionAtlasiP25106. baseline and differential.
GenevisibleiP25106. HS.

Family and domain databases

InterProiIPR001416. ACKR3.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view]
PANTHERiPTHR10489:SF682. PTHR10489:SF682. 1 hit.
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR00646. RDC1ORPHANR.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiACKR3_HUMAN
AccessioniPrimary (citable) accession number: P25106
Secondary accession number(s): A8K6J4
, Q53RV4, Q8NE10, Q92938, Q92986
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 1992
Last sequence update: October 3, 2006
Last modified: November 30, 2016
This is version 169 of the entry and version 3 of the sequence. [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

Caution

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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.