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Chemokines

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


45-1 Ramsey Road, Shirley, NY 11967, USA
USA: 1-631-559-9269  1-631-448-7888
Europe: 44-207-048-3343
FAX: 1-631-938-8127
EMAIL: info@creative-biomart.com

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