The chemokine family of proteins has broad, diverse functional repertoires. However, their structural variation is narrow. Chemokines are small (8-10 kDa), secreted single polypeptide chains 70-100 residues long. Across the family, the proteins have 20-95% amino acid sequence identity (including conserved cysteine residues) and new members are continuing to be identified at a rapid pace; an automated website (http://cytokine.medic.kumamoto-u.ac.jp/CFC/CK/chemokine.html) gives updates of known chemokine sequences as they are reported. Currently, it has been estimated that there are approximately 50-60 human chemokines that are grouped into four “subfamilies” based on their primary sequences: CC-, CXC-, CX₃C-, and C-chemokines. The CC-, CXC-, and CXsC-chemokines are classified based on the number of residues separating the first two conserved cysteine residues. In the CXC-chemokines, a single residue separates the first two of four cysteine residues, while in the CC-chemokines, the first two cysteines are adjacent to each other. The CX3C- and C-chemokine “subfamilies” are composed of one member each in humans; fractalkine and lymophotactin, respectively. The C-chemokine lymophotactin contains only two of the four conserved cysteine residues, while the CX3C-chemokine fractalkine has three intervening residues between the first two cysteines.

Both the CC- and CXC-chemokine subfamilies have many members, and members of the same subfamily resemble each other more (25-80% homology) than members of the other subfamily (10-25% homology). In addition, chemokines within the same subfamily often possess overlapping chemoattractant specificity; thus, CC chemokines commonly attract monocytes, basophils, eosinophils, and T lymphocytes, while CXC chemokines effectively attract neutrophils, lymphocytes, and monocytes. The CC and CXC chemokines are plurifunctional. Thus in addition to chemoattraction these chemokines possess functions that range from regulation of immune function and control of haematopoiesis, to modulation of vascular endothelial-cell action and growth, as well as antiviral defense.

Chemokines mediate their biological activities through G protein-coupled cell surface receptors. These chemokine receptors are found on the surfaces of a wide range of cells, including haematopeoitic and non-haematopoietic cells. Chemokine receptors are primarily associated with the heterotrimeric G_i-type G-protein. Activation of the receptor on the surface causes the exchange of GDP for GTP by the G_i_α subunit of the G_i-protein and subsequent release of G_i_α-GTP from the G_i_βG_i_γ binary complex. The GjpGjy complex activates intracellular proteins such as phospholipase C leading to the downstream release of calcium from the endoplasmic reticulum, while G_i_α-GTP inhibits the activity of adenylate cyclase. Other poorly understood downstream intracellular activities also occur upon chemokine receptor activation; however, the end result leads to leukocyte chemotaxis and release of cellular granules.

The chemokine receptors are named according to their cognate chemokine subfamily classification. For example, CC chemokine receptor 3 (CCR3) interacts with CC chemokines such as eotaxin-1, eotaxin-2, and eotaxin-3 while CXC chemokine receptor 4 (CXCR4) interacts with CXC chemokines such as SDF-1α (stromal cell-derived factor 1α), SDF-1β (stromal cell-derived factor 1β), and PBSF (pre-B-cell growth-stimulating factor). Chemokine receptors, like other G protein-coupled receptors (GPCRs), are part of the superfamily of seven transmembrane receptors (STRs). These receptors are characterized by seven hydrophobic stretches of 20-25 amino acids, predicted to form seven transmembrane helices, connected by alternating extracellular and intracellular loops. The seven transmembrane domains are enriched in hydrophobic amino acids, several of which are conserved among most members of superfamily. Based on statistical analysis of sequences in the hydrophobic domains and the known structures of the STRs bacteriorhodpsin and rhodopsin, a general structural model for STRs has been proposed. The major features are: (1) an extracellular amino-terminus (N-terminus); (2) an intracellular carboxy-terminus (C- terminus); (3) seven helical transmembrane domains (TMDs) oriented perpendicularly to the plasma membrane and kinked helices 1, 4, 5, 6 , and 7 by intrahelical prolines; (4) three intracellular and three extracellular connecting loops composed of hydrophilic amino acids; and (5) disulfide bonds linking cysteine residues in the extracellular loops. For chemokine receptors, disulphide bonds link cysteine residues in the first and second extracellular loops and the N-terminus and third extracellular loop. These structural features create an approximately circular packing arrangement for STRs in which transmembrane segments one and seven are expected to be near each other in the tertiary structure but distant in the primary polypeptide sequence. The intracellular regions of the chemokine receptors are important for G-protein recognition and activation, while the extracellular elements (and possibly transmembrane regions) are involved in chemokine binding. Although the basic topology of chemokine receptors is established (ie. seven transmembrane spanning regions connected by eight hydrophilic regions) the precise structures of the receptors is not known. However, similar to the other GPCRs, the sequence homology among the chemokine receptors is contained primarily within the hydrophobic transmembrane domains and intracellular loop regions while the sequences of the extracellular loops are more divergent.

Chenmokins and their Receptors

Human Chemokines	Alternate Names	Mouse Homolgue	Receptor
CXC
CXCL1	GROα, MGSA	N51/KC, MIP-2	CXCR2
CXCL2	GROβ, M IP-2α	Gro/KC	CXCR2
CXCL3	GROγ, MIP-2β	Gro/KC	CXCR2
CXCL4	Platelet factor-4	None	CXCR2
CXCL5	ENA-78	LIX	CXCR2
CXCL6	GCP-2	LIX	CXCR2
CXCL7	PBP	None	CXCR2
CXCL8	IL-8	None	CXCR1, R2
CXCL9	Mig	Mig	CXCR3
CXCL10	IP-10	CRG-2	CXCR3
CXCL11	I-TAC	None	CXCR3
CXCL12	SDF-Iα, SDF-Iβ	SDF-Iα, SDF-Iβ	CXCR4
CXCL13	BCA-1, BLC	BLC	CXCR5
CXCL14	BRAK, BMAC	BRAK, BMAC	Unknown
CXCL15	None	Lungkine	Unknown
CXCL16	CXCL16	CXCL16	CXCR 6
CC
CCL1	I-309	TCA-3	CCR 8
CCL2	MCP-1	JE	CCR2, 9
CCL3	MIP-1α, LD78α	MIP-1α, LD78α	CCR1, 5, 9
CCL4	MIP-1β	MIP-1β	CCR1, 5, 9
CCL5	RANTES	RANTES	CCR1, 3, 5
CCL6	None	C10, MRP-1	Unknown
CCL7	MCP-3	MARC/FIC	CCR2, 9
CCL8	MCP-2	None	CCR2, 9
CCL9	None	MRP-2, MIP-1γ	Unknow
CCL10	None	None	n/a
CCL11	Eotaxin-1	Eotaxin	CCR3, 9, CXCR3
CCL12	None	MCP-5	CCR2
CCL13	MCP-4	None	CCR2, 3, 9, CXCR3
CCL14	HCC-1	None	CCR9
CCL15	HCC-2,leukotactin-1,MIP-5	None	CCR1, 3
CCL16	FICC-4, monotactin-1, LEC	None	Unknown
CCL17	TARC	None	CCR4
CCL18	DC-CK-1, PARC, MIP-4	None	Unknown
CCL19	MIP-3β,ELC,exodus-3, ckβ11	None	CCR7
CCL20	MIP-3α, LARC, exodus-1	None	CCR6
CCL21	6-Ckine, SLC, exodus-2	6-Ckine, SLC	CCR7, CXCR3
CCL22	MDC	ABCD-1	CCR4
CCL23	MPIF-1, ckβ8	None	CCR1
CCL24	MPIF-2,eotaxin-2, ckβ6	None	CCR3
CCL25	TECK	TECK	Unknown
CCL26	Eotaxin-3, MIP-4α	None	CCR3
CCL27	Eskine	ALP	CCR10
CCL28	MEC	CCL28/MEC	CCR10
C
XCL1	Lymophotactinα, SCM-1α	lymophotactin	XCR1
XCL2	Lymophotactinβ, SCM-1β	None	XCR1
CX₃C
CX₃CL 1	Fractralkine, neurotactin	Fractralkine, neurotactin	CXCR31

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