Proteins are classified into the chemokine family based on the characteristics of chemokine structure. Chemokines are structurally and functionally related 8–10 kDa peptides that are the products of distinct genes clustered on human chromosomes 4 and 17 and can be found at sites of inflammation. They are approximately 20-50% identical to each other; that is, they share gene sequence and amino acid sequence homology. They all also possess conserved amino acids that are important for creating their 3-dimensional or tertiary structure, such as (in most cases) four cysteines that interact with each other in pairs to create a Greek key shape that is a characteristic of chemokines. The chemokine fold is conserved across subfamilies and is composed of a three-stranded anti-parallel beta-sheet, which is preceded by a disordered amino terminus and covered on one side by a carboxy-terminal alpha-helix.
Chemokines are presented on the surface of the endothelial cell through interactions with glycosaminoglycans (GAGs). Some chemokines (such as CXCL8, shown in panel a) bind GAG through amino acids in their C-terminal alpha-helix, whereas others (such as CCL5, shown in panel b) interact with GAGs through residues that are located in the loop connecting the N terminus with the first beta-strand (20s loop) and in the loop connecting the second and the third beta-strands (40s loop). The interaction with the signalling receptor involves multiple regions of both the chemokine and the receptor, with particular relevance for the N-terminal domains. Chemokine receptor conserved motifs that are important for signalling include: an aspartic acid residue, a Thr-X-Pro (TXP; where X denotes any amino acid) motif in the second transmembrane domain, and an Asp-Arg-Tyr (DRY) motif at the boundary of the third transmembrane domain with the second intracellular loop. ELR motif, Glu-Leu-Arg motif.
The three-dimensional structure of each chemokine monomer is virtually identical, but the quaternary structure of chemokines is different for each subfamily. Structure-function studies reveal several regions of chemokines to be involved in function, with the N-terminal region playing a dominant role. A number of proteins and small-molecule antagonists have been identified that inhibit chemokine activities.
Chemokine activity is initiated by the chemokine agonist binding to a specific G protein–coupled receptor. Activation of the chemokine receptor is followed by exchange of bound GDP for GTP in the subunit of the G proteins. The G proteins disassociate from the receptor and activate several effector molecules downstream, which results in a cascade of signaling events within the cytoplasm of the cell. This sequence of events results in diverse physiological processes including leukocyte migration and trafficking, leukocyte degranulation, cell differentiation, and angiogenesis or angiostasis. Although chemokines are traditionally associated with the development and response of the immune system, examples exist that indicate a broader role. Based on knock-out studies of mice, the chemokine CXCL12 (SDF-1) or its receptor, CXCR4, have equivalent phenotypes. Both suffer from impaired fetal development of the cerebellum, the cardiac septum, gastric vasculature, and B-cell lymphopoesis. These mice die either in utero or at birth.
Chemokines have proved central to the process of extravasation of leukocytes, which includes multiple steps involving interactions of adhesion molecules and the chemoattractant function of these proteins. Central to immunity and surveillance by the immune system is the migration of dendritic cells (DCs) to tissues and lymph nodes. Several chemokines regulate the migration of monocytes and immature dendritic cells, which express chemokine receptors such as CCR1, CCR2, CCR5, CCR6, CCR7, and CXCR2.
Larry C, et al. (2003) Cytokines and chemokines. J Allergy Clin Immunol. 111(2 Suppl):S460-75.
Guerreiro R, et al. (2011) The chemokines and their receptors: characteristics and physiological functions. Acta Med Port. 24 Suppl 4:967-76.
Fernandez E, et al. (2002). Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol. 42: 469–99.
Alberto M, et al. (2006). Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nature Reviews Immunology. 6, 907-918.