This gene is one of several chemokine genes clustered on the q-arm of chromosome 17. Chemokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. Specifically, chemokines attract lymphocytes to sites of infection or damage. This protein binds to several chemokine receptors including chemokine binding protein 2 (CCBP2 or D6) and chemokine (C-C motif) receptor 5 (CCR5).
CCR5 is a co-receptor for HIV, and binding of CCL3L1 to CCR5 inhibits HIV entry. Furthermore, the binding causes the receptor to be taken inside the cell by endocytosis, to eventually be reprocessed and re-expressed.[1]
Gene organization
The human genome reference assembly contains two full copies of the gene (CCL3L1 and CCL3L3) and an additional partial duplication, which is thought to result in a pseudogene, designated CCL3L2. This record represents the more telomeric full-length gene.[1]
Clinical significance
The copy number of this gene varies among individuals. This is hypothesized to be due to segmental duplication of the region containing CCL3. Most individuals have 1-6 copies in the diploid genome, although rare individuals have zero or more than six copies. With increased copy number, there is more CCL3L1 expressed, and so competition for the CCR5 binding site is increased. This leads to slower advancement of disease in HIV-infected individuals, giving those with greater copy number more resistance.[1]
↑Hirashima M, Ono T, Nakao M, Nishi H, Kimura A, Nomiyama H, Hamada F, Yoshida MC, Shimada K (1992). "Nucleotide sequence of the third cytokine LD78 gene and mapping of all three LD78 gene loci to human chromosome 17". DNA Sequence : The Journal of DNA Sequencing and Mapping. 3 (4): 203–12. doi:10.3109/10425179209034019. PMID1296815.
↑Miyakawa T, Obaru K, Maeda K, Harada S, Mitsuya H (Feb 2002). "Identification of amino acid residues critical for LD78beta, a variant of human macrophage inflammatory protein-1alpha, binding to CCR5 and inhibition of R5 human immunodeficiency virus type 1 replication". The Journal of Biological Chemistry. 277 (7): 4649–55. doi:10.1074/jbc.M109198200. PMID11734558.
↑Struyf S, Menten P, Lenaerts JP, Put W, D'Haese A, De Clercq E, Schols D, Proost P, Van Damme J (Jul 2001). "Diverging binding capacities of natural LD78beta isoforms of macrophage inflammatory protein-1alpha to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils". European Journal of Immunology. 31 (7): 2170–8. doi:10.1002/1521-4141(200107)31:7<2170::AID-IMMU2170>3.0.CO;2-D. PMID11449371.
Hirashima M, Ono T, Nakao M, Nishi H, Kimura A, Nomiyama H, Hamada F, Yoshida MC, Shimada K (1993). "Nucleotide sequence of the third cytokine LD78 gene and mapping of all three LD78 gene loci to human chromosome 17". DNA Sequence : The Journal of DNA Sequencing and Mapping. 3 (4): 203–12. doi:10.3109/10425179209034019. PMID1296815.
Blum S, Forsdyke RE, Forsdyke DR (March 2009). "Three human homologs of a murine gene encoding an inhibitor of stem cell proliferation". DNA and Cell Biology. 9 (8): 589–602. doi:10.1089/dna.1990.9.589. PMID2271120.
Naruse K, Ueno M, Satoh T, Nomiyama H, Tei H, Takeda M, Ledbetter DH, Coillie EV, Opdenakker G, Gunge N, Sakaki Y, Iio M, Miura R (June 1996). "A YAC contig of the human CC chemokine genes clustered on chromosome 17q11.2". Genomics. 34 (2): 236–40. doi:10.1006/geno.1996.0274. PMID8661057.
Nibbs RJ, Yang J, Landau NR, Mao JH, Graham GJ (June 1999). "LD78beta, a non-allelic variant of human MIP-1alpha (LD78alpha), has enhanced receptor interactions and potent HIV suppressive activity". The Journal of Biological Chemistry. 274 (25): 17478–83. doi:10.1074/jbc.274.25.17478. PMID10364178.
Xin X, Shioda T, Kato A, Liu H, Sakai Y, Nagai Y (Aug 1999). "Enhanced anti-HIV-1 activity of CC-chemokine LD78beta, a non-allelic variant of MIP-1alpha/LD78alpha". FEBS Letters. 457 (2): 219–22. doi:10.1016/S0014-5793(99)01035-2. PMID10471782.
Proost P, Menten P, Struyf S, Schutyser E, De Meester I, Van Damme J (Sep 2000). "Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78beta into a most efficient monocyte attractant and CCR1 agonist". Blood. 96 (5): 1674–80. PMID10961862.
Lambeir AM, Proost P, Durinx C, Bal G, Senten K, Augustyns K, Scharpé S, Van Damme J, De Meester I (Aug 2001). "Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family". The Journal of Biological Chemistry. 276 (32): 29839–45. doi:10.1074/jbc.M103106200. PMID11390394.
Struyf S, Menten P, Lenaerts JP, Put W, D'Haese A, De Clercq E, Schols D, Proost P, Van Damme J (Jul 2001). "Diverging binding capacities of natural LD78beta isoforms of macrophage inflammatory protein-1alpha to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils". European Journal of Immunology. 31 (7): 2170–8. doi:10.1002/1521-4141(200107)31:7<2170::AID-IMMU2170>3.0.CO;2-D. PMID11449371.
Miyakawa T, Obaru K, Maeda K, Harada S, Mitsuya H (Feb 2002). "Identification of amino acid residues critical for LD78beta, a variant of human macrophage inflammatory protein-1alpha, binding to CCR5 and inhibition of R5 human immunodeficiency virus type 1 replication". The Journal of Biological Chemistry. 277 (7): 4649–55. doi:10.1074/jbc.M109198200. PMID11734558.
Modi WS (Apr 2004). "CCL3L1 and CCL4L1 chemokine genes are located in a segmental duplication at chromosome 17q12". Genomics. 83 (4): 735–8. doi:10.1016/j.ygeno.2003.09.019. PMID15028295.