Chemokines
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Chemokines
Chemokine receptors
What is chemokine?
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 Gi-type G-protein. Activation of the receptor on the surface causes the exchange of GDP for GTP by the Giα subunit of the Gi-protein and subsequent release of Giα-GTP from the GiβGiγ binary complex. The GjpGjy complex activates intracellular proteins such as phospholipase C leading to the downstream release of calcium from the endoplasmic reticulum, while Giα-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 |