The chemokine and chemokine receptor superfamilies and their molecular evolution

Abstract

The human chemokine superfamily currently includes at least 46 ligands, which bind to 18 functionally signaling G-protein-coupled receptors and two decoy or scavenger receptors. The chemokine ligands probably comprise one of the first completely known molecular superfamilies. The genomic organization of the chemokine ligand genes and a comparison of their sequences between species shows that tandem gene duplication has taken place independently in the mouse and human lineages of some chemokine families. This means that care needs to be taken when extrapolating experimental results on some chemokines from mouse to human.

Figure 1

A simplified diagram of the human chemokine superfamily, arranged by the receptors they bind to. Chemokines are represented by only their ligand number, and the receptor name also indicates whether each ligand is a CC or CXC; for example, the '6' adjacent to 'CXCR1' represents CXC6. The colors represent the chromosomal location of the ligands: the genes encoding the ligands shown in the same color are at the same chromosomal location. It can be seen that ligands whose genes are located in the same chromosomal location tend to bind to the same receptor. The extra lines attached to CXCL16 and CX3CL1 mean that these proteins exist as transmembrane proteins.

Figure 2

Sequence relationship analysis of the human (h) and mouse (m) (a) chemokines and (b) chemokine receptors. Phylogenetic trees were constructed using amino acid sequences with Clustal X and PAUP* (the neighbor joining method) programs [37]. In (a), the GRO and IP10 groups of CXC chemokines and the MCP and MIP groups of CC chemokines (see also Figure 3) are circled. Red letters indicate proteins that are found in only mouse or human but not the other. Blue letters indicate proteins for which the relationships are uncertain.

Figure 3

Schematic genomic organization of the human and mouse chemokine superfamily. (a) Major-cluster chemokines; (b) mini-cluster chemokines; (c) non-cluster chemokines. Solid arrows indicate chemokine genes and their transcriptional orientation; red, green and pink arrows indicate inflammatory, homeostatic and dual function chemokine genes, respectively, and gray arrows indicate pseudogenes. Duplication units in the major clusters are indicated by open yellow arrows. This figure is based on the NCBI 36 and 35 assemblies of the human and mouse genomes [38]. A gap indicates a region not yet covered by the genome sequencing consortiums, while a dashed line denotes a similar region of more than 1 Mb.

Figure 4

Chemokine and chemokine receptor sequences, such as (a) CXCR4, (b) CXCL12 and (c) CXCL8, are highly conserved throughout evolution, from jawless fish to humans. Identical amino acid residues are highlighted in green; the seven transmembrane regions of the receptors are indicated by black lines; the four conserved cysteine residues are indicated by dots above the sequences. Species abbreviations: dare, Danio rerio (zebrafish); pema, Petromyzon marinus (sea lamprey); lafl, Lampetra fluviatilis (European river lamprey). Accession numbers (from GenBank) are as follows: human CXCR4, NM_003467; zebrafish cxcr4b, NM_131834; sea lamprey cxcr4, AY178969; human CXCL12, NM_000609; zebrafish cxcl12a, NM_178307; zebrafish cxcl12b, NM_198068; human IL-8, NM_000584; river lamprey CXCL8, AJ231072.