Mammalian protein found in Homo sapiens
Chemokine (C-C motif) ligands 4 (also CCL4) previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the "CCL4" gene. "CCL4" belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.
CCL4 is a small cytokine that belongs to the CC chemokine subfamily. CCL4 is being secreted under mitogenic signals and antigens and hereby acts as a chemoattractant for natural killer cells, monocytes and various other immune cells in the site of inflamed or damaged tissue.
Genomics.
In the human genome, CCL4 and many other CC chemokines is encoded by a single gene on chromosome 17 (17q11-q21). The CCL4 gene consists of three exons and two introns which are separated by 14 kb and are organized in a head to head fashion. MIP-1 genes have 3 untranslated gene regions containing a polyadenylation site (AATAAA) and several AT-rich sequences. The CCL4 protein precursor consist of 92 amino acids. In turn, the mature CCL4 protein is 92 amino acids long. The CCL4 predicted Mr weight is 7814.8 Da with no apparent N-linked glycosylation site as in other of the MIP-1 proteins.
Molecular structure.
CCL4 is a polypeptide chain with a molecular weight of approximately 8-10 kDa arranged in a three-dimensional structure in the form of as symmetrical homodimer.
Monomeric subunits in their secondary structure composed by a triple-stranded antiparallel sheet form in a Greek key structure on top of which lies an α-helix. NH2-terminus is arranged as a long loop followed by a four-residue helical turn. The overall form of homodimer is globular elongated and cylindrical with sizes: 56 Å × 30 Å × 26 Å in contrast of monomer structure which is similar to IL-8.
CCL4 as well as other MIP-1s whether human or mouse have a high tendency to self-aggregation. Aggregation as a reversible and dynamic process depends largely on the concentration of chemokine.
The distinction between the CC chemokine families, MIP-1α and MIP-1β, was initially based on whether the first two cysteine residues are separated by one residue (α) or are adjacent (β). Final form of tertiary structure of MIP-1 has been defined by heteronuclear magnetic resonance (NMR) analysis.
Concentration of this chemokine has been shown to be inversely related with MicroRNA-125b. Concentration of CCL4 within the body increases with age, which may cause chronic inflammation and liver damage.
Function.
CCL4 as a chemokine which is produced during inflammation, damage or other important dynamic processes as an angiogenesis to attract immune cells as leukocytes transgress the vascular endothelium and migrate into peripheral tissues.
Production of CCL4
CCL4 is produced by: monocytes, B cells, T cells, NK cells, dendritic cells, neutrophils, fibroblasts, endothelial cells such as vascular smooth muscle cells, brain microvessel endothelial cells, fetal microglia and epithelial cells.
CCL4 is a major HIV-suppressive factor produced by CD8+ T cells.
Perforin-low memory CD8+ T cells that normally synthesize MIP-1-beta.
CCL4 is produced by: neutrophils, monocytes, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells.
Interactions.
CCL4 has been shown to interact with CCL3.
CCL4 binds to G protein-Coupled Receptors CCR5 and CCR8.
References.
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Further reading.
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