CXCR4
CXCR4 | ||
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3D structural model of CXCR4 with the antagonist IT1t | ||
Existing structure data : PDB 3OE9 , PDB 3ODU , PDB 3OE0 , PDB 3OE6 , PDB 3OE8 |
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Properties of human protein | ||
Mass / length primary structure | 352 AS ; 39.7 kDa | |
Secondary to quaternary structure | 7TM | |
Identifier | ||
Gene names | CXCR4 , LESTR, Fusin, CD184 | |
External IDs | ||
Occurrence | ||
Parent taxon | Vertebrates |
CXCR4 (short for CXC motif chemokine receptor 4 , also Stromal cell-derived factor 1 receptor (SDF-1 receptor) , fusin , leukocyte-derived seven transmembrane domain receptor (LESTR) , CD184 ) is a receptor protein from the chemokine receptor family . CXCR4 is widespread in many cells of the hematopoietic system and is particularly expressed by many stem cells and tumor cells. This receptor is activated by the chemokine CXCL12 and the cytokine Macrophage Migration Inhibiting Factor (MIF). CXCR4 plays a key role in the mobilization and targeted migration of stem cells into their storage (e.g. fetal liver , bone marrow ) or their places of use in the formation of organs ( organogenesis ) as well as organ and wound healing . Pathophysiologically, CXCR4 is involved in the growth and metastatic spread of tumors as well as in inflammatory processes. In addition, CXCR4 is the primary co-receptor for T-cell using (T-trope) HI viruses .
Occurrence
Compared to other chemokine receptors, CXCR4 shows a wide distribution within the organism. This receptor can be detected in neutrophils , monocytes , T lymphocytes , B lymphocytes , pre-B cells, dendritic cells , and macrophages within the hematopoietic system . The expression of CXCR4 on CD34- positive progenitor cells is particularly characteristic . In addition, CXCR4 is produced by cells of the blood vessel endothelium , the central nervous system and the gastrointestinal tract . The majority of all tumors are also CXCR4-positive.
biochemistry
structure
CXCR4 is a transmembrane protein from the group of G-protein-coupled receptors that is encoded by a gene on chromosome 2 gene locus q21. Two different gene products are known that arise from alternative splicing . The primary product of protein biosynthesis has a molar mass of about 40 kDa and is subject to further modifications such as glycosylation and sulfation. Recent findings indicate that CXCR4 is in dimeric or oligomeric form. Other receptors (heterodimers or oligomers) can also be involved in these complexes.
Mutations
For CXCR4, mutations have been described which manifest themselves in a change in the receptor properties. Mutations of the coding DNA sequence at positions 1000 or 1013 of the Cxcr4 gene result in a shortened CXCR4 protein that is missing large parts of the intracellular C-terminus of the receptor. Due to the absence of the C-terminus, CXCR4 loses the ability to self-regulate through internalization after activation. The receptor can thus be permanently stimulated. This rare mutation is believed to be a possible cause of WHIM syndrome . Naturally occurring receptor-inactivating mutations, such as those described for the chemokine receptor CCR5, are not known for CXCR4.
Receptor activation
CXCR4 is activated by its ligand CXCL12, whereby the receptor starts an intracellular signal transduction cascade . The binding and activation of CXCL12 to CXCR4 is believed to be a two-step process. In a first step, CXCL12 binds to the extracellular N-terminus of the receptor. The N-terminal end of the chemokine can then dip into the binding pocket of CXCR4, which lies within the transmembrane domains of the receptor, and activate it.
The stimulated receptor then activates a signal transduction cascade in which, among other things, G proteins of the G i family are involved.
function
Stem cell mobilization and anchoring
The main function of CXCR4 is to control the migration of stem cells to sources of CXCL12 such as the bone marrow , lungs and liver . In connection with this, CXCR4 also plays a crucial role in anchoring stem cells in their storage locations and in organogenesis. Knockout mice lacking CXCR4 or its ligand CXCL12 are not viable due to severe organ damage. After birth, CXCR4 plays an important role in angiogenesis , wound healing, and organ repair.
Inflammation
Increased synthesis of CXCL12 in inflamed tissues and a chemotactic effect on CXCR4-expressing lymphocytes has been implicated in a role in inflammatory diseases.
cancer
Since the vast majority of tumors express CXCR4, CXCL12 shows chemotactic effects on most tumor cells. This chemotactic effect is one of the main causes of the formation of metastases , which particularly affect places with high CXCL12 production rates, especially the bone marrow, lungs and liver. In addition, the CXCR4-CXCL12 axis is also involved in tumor growth by promoting angiogenesis.
HIV
Along with the chemokine receptor CCR5, CXCR4 is the most important co-receptor for the docking and penetration of HIV into human cells. The body's own CXCR4 agonist CXCL12 has been shown to have an inhibitory effect on HI viruses . This is attributed to a CXCL12-induced internalization of CXCR4.
pharmacology
Thanks to its role as an HIV co-receptor and its potential involvement in the development and / or spread of cancer and inflammatory diseases, CXCR4 is an attractive target for new drug development. In the early 1990s, screening for HIV-inhibiting substances enabled the development of the selective CXCR4 antagonist and HIV blocker Plerixafor (AMD3100), even before CXCR4 could be identified and characterized. Plerixafor has now been approved as a drug for releasing stem cells into the bloodstream and for subsequent autologous stem cell transplantation. Further developments led to substances with better bioavailability (e.g. AMD070). Independently of this, the elucidation of the pharmacological effects of polyphemusin II in horseshoe crabs led to the development of selective peptide CXCR4 antagonists. However, these have not yet been used therapeutically.
In Porphyromonas gingivalis , the marker germ for severe and aggressive forms of periodontitis , which is responsible for the loss of teeth , the accessory fimbriae ( fimbriae C, D, and E) associate with the long fimbriae and play a role in bonding Host matrix proteins and interaction with the CXCR4. Experiments have shown that the loss of the accessory fimbriae significantly weakens the virulence of the pathogen.
Individual evidence
- ↑ J. Bernhagen, R. Krohn, H. Lue, JL Gregory, A. Zernecke, RR Koenen, M. Dewor, I. Georgiev, A. Schober, L. Leng, T. Kooistra, G. Fingerle-Rowson, P. Ghezzi, R. Kleemann, SR McColl, R. Bucala, MJ Hickey, C. Weber: MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment . In: Nat. Med . 13, No. 5, May 2007, pp. 587-596. doi : 10.1038 / nm1567 . PMID 17435771 .
- ↑ Hernandez PA, Gorlin RJ, Lukens JN, et al : Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease . In: Nat. Genet. . 34, No. 1, May 2003, pp. 70-74. doi : 10.1038 / ng1149 . PMID 12692554 .
- ↑ Gupta SK, Pillarisetti K, Thomas RA, Aiyar N: Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1alpha: implications for development of selective CXCR4 antagonists . In: Immunology letters . 78, No. 1, August 2001, pp. 29-34. doi : 10.1016 / S0165-2478 (01) 00228-0 . PMID 11470148 .
- ↑ Crump MP, Gong JH, Loetscher P, et al : Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1 . In: The EMBO journal . 16, No. 23, December 1997, pp. 6996-7007. doi : 10.1093 / emboj / 16.23.6996 . PMID 9384579 . PMC 1170303 (free full text).
- ↑ Ma Q. et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc. Natl. Acad. Sci. 95: 9448-9453,1998.
- ↑ Nagasawa T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF / SDF-1. Nature 382: 635-637, 1996.
- ↑ Zou YR et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393: 595-599, 1998.
- ↑ Bleul CC et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR / fusin and blocks HIV-1 entry. Nature 382: 829-833, 1996.
- ↑ DL Pierce, S. Nishiyama et al. a .: Host adhesive activities and virulence of novel fimbrial proteins of Porphyromonas gingivalis. In: Infection and Immunity. Volume 77, number 8, August 2009, pp. 3294-3301, doi: 10.1128 / IAI.00262-09 , PMID 19506009 , PMC 2715668 (free full text).