CCR5

from Wikipedia, the free encyclopedia
CC chemokine receptor type 5
CC chemokine receptor type 5

Existing structure data : 1ND8 , 1NE0 , 1OPN , 1OPT , 1OPW , 2L87 , 2MZX , 2RLL , 2RRS , 4MBS

Properties of human protein
Mass / length primary structure 352 amino acids
Secondary to quaternary structure Transmembrane protein
Identifier
Gene names CCR5  ; CC-CKR-5; CCCKR5; CCR-5; CD195; CKR-5; CKR5; CMKBR5; IDDM22
External IDs
Orthologue
human House mouse
Entrez 1234 12774
Ensemble ENSG00000160791 ENSMUSG00000079227
UniProt P51681 P51682
Refseq (mRNA) NM_000579 NM_009917
Refseq (protein) NP_000570 NP_034047
Gene locus Chr 3: 46.37 - 46.38 Mb Chr 9: 124.12 - 124.15 Mb
PubMed search 1234 12774

CCR5 or CC motif chemokine receptor 5 - in addition to CD195 and other synonyms - the name of a receptor protein from the family of chemokine receptors that from gene CCR5 , which is encoded on human chromosome 3 ( gene locus is 3p21.31), and in cells of the immune system such as T cells and macrophages expressed is.

CCR5 is of particular importance because a HI virus 1 uses it as a coreceptor (after binding to CD4 ) in order to attach itself to a cell in such a way that it can be infected.

receptor

The chemokine receptor CCR5 is found as a transmembrane protein on the surface of various leukocytes , for example in macrophages , CD4 + cells, CD8 + cells and NKT cells . CCR5 is activated by different ligands such as CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES) and CCL8 (MCP-2), enables chemotactic cell movement and is thus involved in inflammatory reactions .

Pathological importance

Attachment of HIV to a CD4 + T helper cell : the viral gp120 protein initially binds to CD4, but only reaches the cell membrane via the binding of the variable loop of gp120 to a coreceptor - CCR5 or CXCR4 - in such a way that penetration is possible via gp41 .

The CCR5 receptor is a co-receptor for HIV infection and makes it possible for HI viruses to dock on macrophages, as well as various T lymphocytes , to penetrate the cells and thus their infection . The development of drugs that inhibit the binding of HIV to CCR5 is therefore of great interest and led, for example, to the first approved entry inhibitor, Maraviroc .

In addition, CCR5 has been implicated in autoimmune diseases such as multiple sclerosis , rheumatoid arthritis and type I diabetes mellitus .

Gene mutation

Transmembrane - domains in the amino acid sequence of CCR5
( C terminus bottom right of the picture)

A mutation of the CCR5 gene with the designation CCR5Δ32 (CCR5-Delta32) , in which a 32 base pair segment is deleted , leads to a frame shift with a premature stop codon . The resulting shortened protein - which lacks the three C-terminal transmembrane domains - remains in the cytoplasm and does not appear on the cell surface .

In the case of a homozygous carrier of the gene mutation, this results in resistance to most HIV strains. Such a homozygous genotype would be expected in the Hardy-Weinberg equilibrium in around 1% of today's Europeans, since the allele frequency is around 10%. The reason for the frequent occurrence of this mutation was initially assumed to be a selection pressure from epidemics in Northern Europe around 700 years ago. However, more recent studies suggest a significantly older age for the occurrence of the mutation and its spread through selection effects. A statement about the selection factor is almost impossible.

The only cure for an HIV infection documented to date was achieved by a bone marrow transplant from a homozygous CCR5Δ32 donor in an HIV-infected person. The HIV-positive man, later known as "The Berlin Patient" , needed a bone marrow transplant due to an AML . After the transplant of the homozygous CCR5Δ32 bone marrow, no virus could be detected in the patient's body after some latency and he is not dependent on HAART today.

In addition, a study published in the Journal of Experimental Medicine in January 2006 suggests that susceptibility to the West Nile virus is massively promoted by the same mutation. The assumption was confirmed two years later by a meta-analysis of the data from the West Nile outbreak in the USA.

Genetic engineering

The Chinese scientist He Jiankui says he has deactivated the CCR5 receptor in several human embryos in order to make the children that were born immune to HIV.

Individual evidence

  1. ↑ so also CKR-5, CC-CKR-5, CMKBR5, IDDM22; see entry in HGNC .
  2. ↑ see entry CCR5 on NCBI.
  3. ↑ Murphy PM, Baggiolini M, Charo IF, et al. : International union of pharmacology. XXII. Nomenclature for chemokine receptors . In: Pharmacological Reviews . 52, No. 1, March 2000, pp. 145-76. PMID 10699158 .
  4. ↑ Galvani AP, Slatkin M: Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele . In: Proc. Natl. Acad. Sci. USA . 100, No. 25, December 2003, pp. 15276-9. doi : 10.1073 / pnas.2435085100 . PMID 14645720 . PMC 299980 (free full text).
  5. ↑ Biloglav Z, Zgaga L, Smoljanović M, et al. : Historic, demographic, and genetic evidence for increased population frequencies of CCR5Delta32 mutation in Croatian Island isolates after lethal 15th century epidemics . In: Croat. Med. J. . 50, No. 1, February 2009, pp. 34-42. PMID 19260142 . PMC 2657566 (free full text).
  6. ↑ Zawicki P, Witas HW: HIV-1 protecting CCR5 Delta32 allele in medieval Poland . In: Infect. Genet. Evol. . 8, No. 2, March 2008, pp. 146-51. doi : 10.1016 / j.meegid.2007.11.003 . PMID 18162443 .
  7. ↑ Faure E, Royer-Carenzi M: Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion? . In: Infect. Genet. Evol. . 8, No. 6, December 2008, pp. 864-74. doi : 10.1016 / j.meegid.2008.08.007 . PMID 18790087 .
  8. ↑ Kerstin Decker: AIDS healing: Anatomy of a miracle. Der Tagesspiegel , June 6, 2011, accessed on March 8, 2014 .
  9. ↑ Hartmut Wewetzer: Guessing the "Berlin patient". Der Tagesspiegel , June 13, 2012, accessed on March 8, 2014 .
  10. ^ WG Glass, DH McDermott et al. a .: CCR5 deficiency increases risk of symptomatic West Nile virus infection. In: The Journal of experimental medicine Volume 203, Number 1, January 2006, pp. 35-40. doi : 10.1084 / jem.20051970 . PMID 16418398 . PMC 211808 (free full text).
  11. ↑ JK Lim, CY Louie et al. a .: Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic. In: The Journal of Infectious Diseases Volume 197, Number 2, January 2008, pp. 262-265. doi : 10.1086 / 524691 . PMID 18179388 .
  12. ↑ https://www.zeit.de/wissen/gesundheit/2018-11/emmanuelle-charpentier-crispr-babys-china-genschere-entsetzt Crispr discoverer criticizes genetic experiments on babies, Zeit online

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