DARC (protein)

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DARC
Properties of human protein
Mass / length primary structure 336 AS ; 35.5  kDa
Secondary to quaternary structure 7TM
Identifier
Gene names DARC , Duffy antigen receptor for chemokines, Duffy receptor, Duffy antigen, Duffy factor, CD234
External IDs
Occurrence
Parent taxon Vertebrates

DARC (from Duffy antigen / receptor for chemokines ), also known as Duffy factor , Duffy antigen or Duffy receptor , is a protein found in the cell membrane of red blood cells , endothelial cells and nerve cells of vertebrates . DARC is a receptor from the chemokine receptor family that binds both inflammatory chemokines with CC and those with CXC motif. Although it can be phylogenetically and structurally assigned to the G protein-coupled receptor due to its seven helices spanning the cell membrane , it is not capable of transmitting signals via G proteins . Its physiological role is largely unclear. A function as a chemokine catcher or as a transporter for chemokines through the endothelium is discussed. Pathophysiologically , the receptor plays an important role in the docking of the malaria pathogens Plasmodium vivax and Plasmodium knowlesi with red blood cells.

The receptor owes its full name to a patient named "Duffy", in whose blood it was detected in 1950 as an antigen responsible for transfusion reactions . With the second antigen found in 1951, a blood group emerged in which three antibodies are now differentiated in humans.

Occurrence

RNA for DARC can be detected in relevant quantities, especially in reticulocytes , the immediate precursor cells of erythrocytes. It is also responsible for the occurrence of the DARC protein in the membrane of mature erythrocytes. In addition, DARC-RNA is also found in various organs such as the brain , the spleen , the bone marrow and the lungs . Expression on endothelial cells of venules and in Purkinje cells of the cerebellum is also characteristic .

biochemistry

genetics

DARC is a membrane protein encoded by a gene on chromosome 1 and the gene locus 1q21-q22. Alternative splicing leads to two different splice variants that differ in their extracellular N-terminal amino acid sequence. The polymorphism of DARC is responsible for the different phenotypes of the Duffy blood group system. A polymorphism at position 42 of the amino acid sequence leads to the phenotypes Fy (a + b-), Fy (a-b +) and Fy (a + b +). A homozygous polymorphism in the promoter region of DARC, which occurs with a frequency of over 90% in Africa, leads to the Duffy-negative Fy (ab -) phenotype with a lack of expression of the antigen on erythrocytes.

structure

Like the chemokine receptors related to it, DARC is structurally characterized by its seven helices spanning the cell membrane. The amino acid sequence shows about 25% structural homology to other chemokine receptors. Nevertheless, the receptor protein lacks the DRY and NPXXY motifs which are characteristic of G protein-coupled receptors of the rhodopsin family (class A) and which are associated with the activation of G proteins.

Receptor activation and signal transduction

DARC is able to bind a number of inflammatory chemokines. In contrast to other chemokine receptors, it shows no selectivity for either CC or CXC chemokines. CXCL1 , CXCL7 , CXCL8 , CCL2 and CCL5 have the highest affinity . After ligand binding, DARC is not capable of signal transduction via G proteins. Other signal transduction pathways via this receptor have not yet been detected either. In contrast to other chemokine receptors, no direct chemotactic effects are detectable for DARC . Only cellular uptake and transcytosis of the bound chemokines suggests a possible role for the receptor in the storage, breakdown or transport of inflammatory chemokines.

function

Inflammation

The selective binding of inflammatory chemokines and an increased expression in the inflamed tissue indicate that DARC is involved in inflammatory processes.

malaria

The role of DARC as an entry receptor for the malaria pathogens Plasmodium vivax and Plasmodium knowlesi in erythrocytes has been researched best . Duffy-negative persons (Fy (ab -) phenotype) who are unable to form a DARC on erythrocytes as a result of a polymorphism in the promoter region, show resistance to these malaria pathogens. The associated selection pressure on the African continent meant that this phenotype dominated particularly in equatorial and southern Africa.

The binding to DARC Duffy binding protein of Plasmodium vivax is a target for the development of therapeutic antibodies and vaccines against the pathogens caused by this form of malaria.

Individual evidence

  1. ↑ Horne K, Woolley IJ: Shedding light on DARC: the role of the Duffy antigen / receptor for chemokines in inflammation, infection and malignancy . In: Inflamm. Res. . 58, No. 8, August 2009, pp. 431-5. doi : 10.1007 / s00011-009-0023-9 . PMID 19290478 .
  2. ↑ a b c Murphy PM, Baggiolini M, Charo IF, et al. : International union of pharmacology. XXII. Nomenclature for chemokine receptors . In: Pharmacol. Rev. . 52, No. 1, March 2000, pp. 145-76. PMID 10699158 .
  3. ↑ a b Pruenster M, Rot A: Throwing light on DARC . In: Biochem Soc Trans . 34, No. Pt 6, December 2006, pp. 1005-8. doi : 10.1042 / BST0341005 . PMID 17073738 .
  4. ^ Walton RT, Rowland-Jones SL: HIV and chemokine binding to red blood cells - DARC matters . In: Cell Host Microbe . 4, No. 1, July 2008, pp. 3-5. doi : 10.1016 / j.chom.2008.06.006 . PMID 18621004 .
  5. ↑ de Brevern AG, Autin L, Colin Y, Bertrand O, Etchebest C: In silico studies on DARC . In: Infect Disord Drug Targets . 9, No. 3, June 2009, pp. 289-303. PMID 19519483 .
  6. ↑ Beeson JG, Crabb BS: Towards a vaccine against Plasmodium vivax malaria . In: PLoS Med . 4, No. 12, December 2007, p. E350. doi : 10.1371 / journal.pmed.0040350 . PMID 18092888 . PMC 2140083 (free full text).
  7. ↑ Grimberg BT, Udomsangpetch R, Xainli J, et al. : Plasmodium vivax invasion of human erythrocytes inhibited by antibodies directed against the Duffy binding protein . In: PLoS Med. . 4, No. 12, December 2007, p. E337. doi : 10.1371 / journal.pmed.0040337 . PMID 18092885 . PMC 2140086 (free full text).