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O00590 (ACKR2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Atypical chemokine receptor 2
Alternative name(s):
C-C chemokine receptor D6
Chemokine receptor CCR-10
Chemokine receptor CCR-9
Chemokine-binding protein 2
Chemokine-binding protein D6
Gene names
Name:ACKR2
Synonyms:CCBP2, CCR10, CMKBR9, D6
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length384 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway results in up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. By scavenging chemokines in tissues, on the surfaces of lymphatic vessels, and in placenta, plays an essential role in the resolution (termination) of the inflammatory response and in the regulation of adaptive immune responses. Plays a major role in the immune silencing of macrophages during the resolution of inflammation. Acts as a regulator of inflammatory leukocyte interactions with lymphatic endothelial cells (LECs) and is required for immature/mature dendritic cells discrimination by LECs. Ref.14 Ref.17

Subcellular location

Early endosome. Recycling endosome. Cell membrane; Multi-pass membrane protein. Note: Predominantly localizes to endocytic vesicles, and upon stimulation by the ligand is internalized via clathrin-coated pits. Once internalized, the ligand dissociates from the receptor, and is targeted to degradation while the receptor is recycled back to the cell membrane. Ref.8 Ref.17

Tissue specificity

Found in endothelial cells lining afferent lymphatics in dermis and lymph nodes. Also found in lymph nodes subcapsular and medullary sinuses, tonsillar lymphatic sinuses and lymphatics in mucosa and submucosa of small and large intestine and appendix. Also found in some malignant vascular tumors. Expressed at high levels in Kaposi sarcoma-related pathologies. Expressed on apoptotic neutrophils (at protein level). Expressed primarily in placenta and fetal liver, and found at very low levels in the lung and lymph node. Ref.7 Ref.11 Ref.14

Induction

By interleukin-6 and interferon-gamma. Ref.14

Domain

The C-terminal cytoplasmic tail controls its phosphorylation, stability, intracellular trafficking itinerary, and chemokine scavenging properties.

Post-translational modification

Phosphorylated on serine residues in the C-terminal cytoplasmic tail. Ref.8

Sequence similarities

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

Ontologies

Keywords
   Biological processInflammatory response
   Cellular componentCell membrane
Endosome
Membrane
   Coding sequence diversityPolymorphism
   DomainTransmembrane
Transmembrane helix
   Molecular functionG-protein coupled receptor
Receptor
Transducer
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG-protein coupled receptor signaling pathway

Traceable author statement Ref.1. Source: ProtInc

chemokine-mediated signaling pathway

Traceable author statement Ref.1. Source: GOC

chemotaxis

Traceable author statement Ref.1. Source: ProtInc

immune response

Traceable author statement Ref.1. Source: ProtInc

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

multicellular organismal development

Traceable author statement Ref.1. Source: ProtInc

neutrophil activation

Inferred from electronic annotation. Source: InterPro

receptor-mediated endocytosis

Inferred from mutant phenotype Ref.17. Source: GOC

   Cellular_componentactin filament

Inferred from direct assay Ref.17. Source: UniProtKB

early endosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

integral component of plasma membrane

Traceable author statement Ref.1. Source: ProtInc

plasma membrane

Inferred from direct assay Ref.17. Source: UniProtKB

recycling endosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionC-C chemokine receptor activity

Inferred from electronic annotation. Source: Ensembl

C-X-C chemokine receptor activity

Inferred from electronic annotation. Source: InterPro

chemokine receptor activity

Traceable author statement Ref.1. Source: ProtInc

scavenger receptor activity

Inferred from mutant phenotype Ref.17. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 384384Atypical chemokine receptor 2
PRO_0000069219

Regions

Topological domain1 – 5050Extracellular Potential
Transmembrane51 – 7121Helical; Name=1; Potential
Topological domain72 – 9221Cytoplasmic Potential
Transmembrane93 – 11321Helical; Name=2; Potential
Topological domain114 – 1185Extracellular Potential
Transmembrane119 – 14022Helical; Name=3; Potential
Topological domain141 – 16222Cytoplasmic Potential
Transmembrane163 – 18321Helical; Name=4; Potential
Topological domain184 – 21734Extracellular Potential
Transmembrane218 – 23821Helical; Name=5; Potential
Topological domain239 – 25012Cytoplasmic Potential
Transmembrane251 – 27121Helical; Name=6; Potential
Topological domain272 – 29322Extracellular Potential
Transmembrane294 – 31421Helical; Name=7; Potential
Topological domain315 – 38470Cytoplasmic Potential
Region327 – 38458C-terminal cytoplasmic tail

Amino acid modifications

Glycosylation191N-linked (GlcNAc...) Potential
Disulfide bond117 ↔ 195 By similarity

Natural variations

Natural variant411V → A.
Corresponds to variant rs2228467 [ dbSNP | Ensembl ].
VAR_049379
Natural variant2481A → V.
Corresponds to variant rs2228469 [ dbSNP | Ensembl ].
VAR_049380
Natural variant3111L → V.
Corresponds to variant rs6779520 [ dbSNP | Ensembl ].
VAR_049381
Natural variant3731Y → S. Ref.5
Corresponds to variant rs2228468 [ dbSNP | Ensembl ].
VAR_024252

Experimental info

Sequence conflict171S → A in AAB97728. Ref.1
Sequence conflict1611S → N in AAB97728. Ref.1
Sequence conflict3561Q → L in AAB97728. Ref.1

Sequences

Sequence LengthMass (Da)Tools
O00590 [UniParc].

Last modified May 2, 2002. Version 2.
Checksum: 464C5703C1DE9A6A

FASTA38443,443
        10         20         30         40         50         60 
MAATASPQPL ATEDADSENS SFYYYDYLDE VAFMLCRKDA VVSFGKVFLP VFYSLIFVLG 

        70         80         90        100        110        120 
LSGNLLLLMV LLRYVPRRRM VEIYLLNLAI SNLLFLVTLP FWGISVAWHW VFGSFLCKMV 

       130        140        150        160        170        180 
STLYTINFYS GIFFISCMSL DKYLEIVHAQ PYHRLRTRAK SLLLATIVWA VSLAVSIPDM 

       190        200        210        220        230        240 
VFVQTHENPK GVWNCHADFG GHGTIWKLFL RFQQNLLGFL LPLLAMIFFY SRIGCVLVRL 

       250        260        270        280        290        300 
RPAGQGRALK IAAALVVAFF VLWFPYNLTL FLHTLLDLQV FGNCEVSQHL DYALQVTESI 

       310        320        330        340        350        360 
AFLHCCFSPI LYAFSSHRFR QYLKAFLAAV LGWHLAPGTA QASLSSCSES SILTAQEEMT 

       370        380 
GMNDLGERQS ENYPNKEDVG NKSA 

« Hide

References

« Hide 'large scale' references
[1]"Cloning, expression, and chromosomal mapping of a novel human CC-chemokine receptor (CCR10) that displays high-affinity binding for MCP-1 and MCP-3."
Bonini J.A., Martin S.K., Dralyuk F., Roe M.W., Philipson L.H., Steiner D.F.
DNA Cell Biol. 16:1249-1256(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Lung.
[2]"Cloning and characterization of a novel promiscuous human beta-chemokine receptor D6."
Nibbs R.J.B., Wylie S.M., Yang J., Landau N.R., Graham G.J.
J. Biol. Chem. 272:32078-32083(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"cDNA clones of human proteins involved in signal transduction sequenced by the Guthrie cDNA resource center (www.cdna.org)."
Kopatz S.A., Aronstam R.S., Sharma S.V.
Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT SER-373.
Tissue: Placenta.
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Liver and Placenta.
[7]"The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors."
Nibbs R.J.B., Kriehuber E., Ponath P.D., Parent D., Qin S., Campbell J.D., Henderson A., Kerjaschki D., Maurer D., Graham G.J., Rot A.
Am. J. Pathol. 158:867-877(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[8]"Multiple roles for the C-terminal tail of the chemokine scavenger D6."
McCulloch C.V., Morrow V., Milasta S., Comerford I., Milligan G., Graham G.J., Isaacs N.W., Nibbs R.J.
J. Biol. Chem. 283:7972-7982(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: C-TERMINAL CYTOPLASMIC TAIL, SUBCELLULAR LOCATION, PHOSPHORYLATION.
[9]Erratum
McCulloch C.V., Morrow V., Milasta S., Comerford I., Milligan G., Graham G.J., Isaacs N.W., Nibbs R.J.
J. Biol. Chem. 288:26820-26820(2013)
[10]"Chemokine decoy receptors: structure-function and biological properties."
Bonecchi R., Savino B., Borroni E.M., Mantovani A., Locati M.
Curr. Top. Microbiol. Immunol. 341:15-36(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[11]"The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation."
Pashover-Schallinger E., Aswad M., Schif-Zuck S., Shapiro H., Singer P., Ariel A.
FASEB J. 26:3891-3900(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[12]"The biochemistry and biology of the atypical chemokine receptors."
Graham G.J., Locati M., Mantovani A., Rot A., Thelen M.
Immunol. Lett. 145:30-38(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[13]"Atypical chemokine receptors: from silence to sound."
Cancellieri C., Vacchini A., Locati M., Bonecchi R., Borroni E.M.
Biochem. Soc. Trans. 41:231-236(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[14]"An analysis of the function and expression of D6 on lymphatic endothelial cells."
McKimmie C.S., Singh M.D., Hewit K., Lopez-Franco O., Le Brocq M., Rose-John S., Lee K.M., Baker A.H., Wheat R., Blackbourn D.J., Nibbs R.J., Graham G.J.
Blood 121:3768-3777(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION, TISSUE SPECIFICITY.
[15]"Regulation of the immune and inflammatory responses by the 'atypical' chemokine receptor D6."
Graham G.J., Locati M.
J. Pathol. 229:168-175(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[16]"Review: Structure-function and biological properties of the atypical chemokine receptor D6."
Cancellieri C., Caronni N., Vacchini A., Savino B., Borroni E.M., Locati M., Bonecchi R.
Mol. Immunol. 55:87-93(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[17]"Beta-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6."
Borroni E.M., Cancellieri C., Vacchini A., Benureau Y., Lagane B., Bachelerie F., Arenzana-Seisdedos F., Mizuno K., Mantovani A., Bonecchi R., Locati M.
Sci. Signal. 6:RA30-RA30(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U94888 mRNA. Translation: AAB97728.1.
Y12815 mRNA. Translation: CAA73346.1.
AY262687 Genomic DNA. Translation: AAP20651.1.
BT006800 mRNA. Translation: AAP35446.1.
AK313561 mRNA. Translation: BAG36335.1.
BC008816 mRNA. Translation: AAH08816.1.
BC011631 mRNA. Translation: AAH11631.1.
BC020558 mRNA. Translation: AAH20558.1.
BC101629 mRNA. Translation: AAI01630.1.
BC112045 mRNA. Translation: AAI12046.1.
RefSeqNP_001287.2. NM_001296.4.
UniGeneHs.146346.

3D structure databases

ProteinModelPortalO00590.
SMRO00590. Positions 36-328.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107643. 8 interactions.
MINTMINT-6631488.
STRING9606.ENSP00000273145.

Protein family/group databases

GPCRDBSearch...

PTM databases

PhosphoSiteO00590.

Proteomic databases

PaxDbO00590.
PRIDEO00590.

Protocols and materials databases

DNASU1238.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000273145; ENSP00000273145; ENSG00000144648.
ENST00000422265; ENSP00000416996; ENSG00000144648.
ENST00000442925; ENSP00000396150; ENSG00000144648.
GeneID1238.
KEGGhsa:1238.
UCSCuc003cme.3. human.

Organism-specific databases

CTD1238.
GeneCardsGC03P042846.
HGNCHGNC:1565. ACKR2.
HPAHPA013819.
MIM602648. gene.
neXtProtNX_O00590.
PharmGKBPA26139.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG297330.
HOGENOMHOG000234122.
HOVERGENHBG106917.
InParanoidO00590.
KOK04187.
OMAHCCFTPI.
OrthoDBEOG7HMS1P.
PhylomeDBO00590.
TreeFamTF330966.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.

Gene expression databases

BgeeO00590.
CleanExHS_CCBP2.
HS_CCR10.
GenevestigatorO00590.

Family and domain databases

Gene3D1.20.1070.10. 1 hit.
InterProIPR001277. Chemokine_CXCR4.
IPR000355. Chemokine_rcpt.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view]
PANTHERPTHR24227. PTHR24227. 1 hit.
PfamPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSPR00657. CCCHEMOKINER.
PR00645. CXCCHMKINER4.
PR00237. GPCRRHODOPSN.
PROSITEPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiCCBP2.
GenomeRNAi1238.
NextBio5057.
PROO00590.
SOURCESearch...

Entry information

Entry nameACKR2_HUMAN
AccessionPrimary (citable) accession number: O00590
Secondary accession number(s): B2R8Y8 expand/collapse secondary AC list , O00537, Q53YA1, Q86UN9, Q96A02
Entry history
Integrated into UniProtKB/Swiss-Prot: June 20, 2001
Last sequence update: May 2, 2002
Last modified: April 16, 2014
This is version 130 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 3

Human chromosome 3: entries, gene names and cross-references to MIM

7-transmembrane G-linked receptors

List of 7-transmembrane G-linked receptor entries