Chemokine

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Chemokines
)
Small cytokines (intecrine/chemokine), interleukin-8 like
SCOP2
3il8 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1dokA:24-90 1dol :24-90 1donA:24-90

1mcaB:29-90 1ml0D:24-90 1domB:24-90 1bo0 :24-90 1ncvB:24-90 1esrA:24-90 1eot :24-88 2eot :24-88 1eihA:27-89 1eigA:27-89 1je4A:24-89 1hunA:24-89 1humA:24-89 1b53B:24-88 1b50B:24-88 1eqtB:26-88 1rtoB:24-88 1u4rD:24-88 1hrjB:24-88 1u4pB:24-88 1b3aB:25-88 1rtnA:24-88 1u4lA:24-88 1u4mA:24-88 1g91A:45-109 2hcc :48-108 1zxtA:26-91 1vmpA:26-89 1cm9B:26-89 1hfgA:26-89 1hfnA:26-89 1hhvA:26-89 1hffA:26-33 1g2sA:24-88 1g2tA:24-88 1j8iA:23-84 1j9oA:23-84 1el0A:24-88 1nr4A:24-88 1nr2A:24-88 1f2lB:26-89 1b2tA:26-89 1m8aA:27-89 1ha6A:28-90 2il8A:29-93 1ilpA:28-93 1qe6A:28-93 1ikm :31-93 3il8 :32-93 1ikl :31-93 1icwB:34-93 1ilqB:28-93 1il8B:29-93 1tvxC:61-121 1napD:59-121 1f9pA:54-121 1mgsB:35-101 1mshA:35-101 1msgA:35-101 1mi2A:28-94 1rhpD:38-98 1f9sB:32-98 1pfmC:39-98 1f9rD:32-98 1pfnA:39-98 1f9qD:32-98 1dn3A:87-98 1plfD:21-82 1rjtA:22-89 1o7zB:22-89 1o7yB:22-89 1o80A:22-89 1lv9A:22-89 1sdf :22-87 1qg7B:22-87

1a15B:29-85 2sdf :22-87 1vmcA:22-87

Chemokines (from

Ancient Greek χῠμείᾱ (khumeíā) 'alchemy', and κῑ́νησῐς (kī́nēsis) 'movement'), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells.[1][2] In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.[1][3]

Cytokine proteins are classified as chemokines according to behavior and structural characteristics. In addition to being known for mediating chemotaxis, chemokines are all approximately 8–10

kilodaltons in mass and have four cysteine
residues in conserved locations that are key to forming their 3-dimensional shape.

These proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Some chemokines are considered pro-

homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been found in other invertebrates
.

Chemokines have been classified into four main subfamilies: CXC, CC, CX3C and C. All of these proteins exert their biological effects by interacting with

transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.[4]

Function

Chemokines released by infected or damaged cells form a concentration gradient. Attracted cells move through the gradient towards the higher concentration of chemokine.

The major role of chemokines is to act as a chemoattractant to guide the migration of cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. Some chemokines control cells of the

leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system
.

Types by function

Chemokines are functionally divided into two groups:[5]

Homing

The main function of chemokines is to manage the migration of

homeostatic
processes.

Basal: homeostatic chemokines are basal produced in the

lymph nodes. As well CXCL12 (SDF-1) constitutively produced in the bone marrow promotes proliferation of progenitor B cells in the bone marrow microenvironment.[7][8]

Inflammatory:

CXCL8. A typical example is CXCL-8, which acts as a chemoattractant for neutrophils. In contrast to the homeostatic chemokine receptors, there is significant promiscuity (redundancy) associated with binding receptor and inflammatory chemokines. This often complicates research on receptor-specific therapeutics in this area.[8]

Types by cell attracted

  • Monocytes / macrophages: the key chemokines that attract these cells to the site of inflammation include: CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL17 and CCL22.
  • T-cell activation and activated T-cells are attracted to sites of inflammation where the IFN-y inducible chemokines CXCL9, CXCL10 and CXCL11 are secreted.[9]
  • CXCL8
    might be inhibitory of mast cells.
  • Eosinophils: the migration of eosinophils into various tissues involved several chemokines of CC family: CCL11, CCL24, CCL26, CCL5, CCL7, CCL13, and CCL3. Chemokines CCL11 (eotaxin) and CCL5 (RANTES) acts through a specific receptor CCR3 on the surface of eosinophils, and eotaxin plays an essential role in the initial recruitment of eosinophils into the lesion.
  • Neutrophils: are regulated primarily by CXC chemokines. An example CXCL8 (IL-8) is chemoattractant for neutrophils and also activating their metabolic and degranulation.[10]

Structural characteristics

disulfide bonds between conserved cysteine
residues.

Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells. All chemokines are small, with a

β-strands and a C-terminal α-helix. These helices and strands are connected by turns called 30s, 40s and 50s loops; the third and fourth cysteines are located in the 30s and 50s loops.[11]

Types by structure

The four chemokine subfamilies
CC chemokines
Name Gene Other name(s) Receptor Uniprot
CCL1 Scya1 I-309, TCA-3
CCR8
CCL2 Scya2 MCP-1 CCR2 P13500
CCL3 Scya3 MIP-1a CCR1 P10147
CCL4 Scya4 MIP-1β CCR1, CCR5 P13236
CCL5 Scya5 RANTES CCR5 P13501
CCL6 Scya6 C10, MRP-2 CCR1 P27784
CCL7 Scya7 MARC, MCP-3 CCR2 P80098
CCL8 Scya8 MCP-2 CCR1, CCR2, CCR5 P80075
CCL10
Scya9 MRP-2, CCF18, MIP-1? CCR1 P51670
CCL11 Scya11 Eotaxin CCR2, CCR3, CCR5 P51671
CCL12 Scya12 MCP-5 Q62401
CCL13 Scya13 MCP-4, NCC-1, Ckβ10 CCR2, CCR3, CCR5 Q99616
CCL14 Scya14 HCC-1, MCIF, Ckβ1, NCC-2, CCL CCR1 Q16627
CCL15 Scya15 Leukotactin-1, MIP-5, HCC-2, NCC-3 CCR1, CCR3 Q16663
CCL16 Scya16 LEC, NCC-4, LMC, Ckβ12
CCR8
O15467
CCL17 Scya17 TARC, dendrokine, ABCD-2 CCR4 Q92583
CCL18 Scya18 PARC, DC-CK1, AMAC-1, Ckβ7, MIP-4 P55774
CCL19 Scya19 ELC, Exodus-3, Ckβ11
CCR7
Q99731
CCL20 Scya20 LARC, Exodus-1, Ckβ4
CCR6
P78556
CCL21 Scya21 SLC, 6Ckine, Exodus-2, Ckβ9, TCA-4
CCR7
O00585
CCL22 Scya22 MDC, DC/β-CK CCR4 O00626
CCL23 Scya23 MPIF-1, Ckβ8, MIP-3, MPIF-1 CCR1 P55773
CCL24 Scya24 Eotaxin-2, MPIF-2, Ckβ6 CCR3 O00175
CCL25 Scya25 TECK, Ckβ15 CCR9 O15444
CCL26 Scya26 Eotaxin-3, MIP-4a, IMAC, TSC-1 CCR3 Q9Y258
CCL27
Scya27 CTACK, ILC, Eskine, PESKY, skinkine CCR10 Q9Y4X3
CCL28 Scya28 MEC CCR3, CCR10 Q9NRJ3
CXC chemokines
Name Gene Other name(s) Receptor Uniprot
CXCL1 Scyb1 Gro-a, GRO1, NAP-3, KC
CXCR2
P09341
CXCL2 Scyb2 Gro-β, GRO2, MIP-2a
CXCR2
P19875
CXCL3 Scyb3 Gro-?, GRO3, MIP-2β
CXCR2
P19876
CXCL4
Scyb4 PF-4 CXCR3B P02776
CXCL5 Scyb5 ENA-78
CXCR2
P42830
CXCL6 Scyb6 GCP-2
CXCR2
P80162
CXCL7 Scyb7 NAP-2, CTAPIII, β-Ta, PEP P02775
CXCL8 Scyb8 IL-8, NAP-1, MDNCF, GCP-1
CXCR2
P10145
CXCL9 Scyb9 MIG, CRG-10 CXCR3 Q07325
CXCL10 Scyb10 IP-10, CRG-2 CXCR3 P02778
CXCL11 Scyb11 I-TAC, β-R1, IP-9
CXCR7
O14625
CXCL12
Scyb12 SDF-1, PBSF
CXCR7
P48061
CXCL13 Scyb13 BCA-1, BLC CXCR5 O43927
CXCL14 Scyb14 BRAK, bolekine O95715
CXCL15 Scyb15 Lungkine, WECHE Q9WVL7
CXCL16 Scyb16 SRPSOX CXCR6 Q9H2A7
CXCL17 VCC-1 DMC, VCC-1 Q6UXB2
C chemokines
Name Gene Other name(s) Receptor Uniprot
XCL1 Scyc1 Lymphotactin a, SCM-1a, ATAC XCR1 P47992
XCL2 Scyc2 Lymphotactin β, SCM-1β XCR1 Q9UBD3
CX3C chemokines
Name Gene Other name(s) Receptor Uniprot
CX3CL1 Scyd1 Fractalkine, Neurotactin, ABCD-3
CX3CR1
P78423

Members of the chemokine family are divided into four groups depending on the spacing of their first two cysteine residues. Thus the nomenclature for chemokines is, e.g.: CCL1 for the ligand 1 of the CC-family of chemokines, and CCR1 for its respective receptor.

CC chemokines

The CC chemokine (or β-chemokine) proteins have two adjacent cysteines (

amino terminus
. There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokine
dendritic cells
.

Examples of CC chemokine include monocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages.

CCL5 (or

RANTES) attracts cells such as T cells, eosinophils and basophils that express the receptor CCR5
.

Increased

aging (and reduced neurogenesis) in mice and humans.[13]

CXC chemokines

The two N-terminal cysteines of CXC chemokines (or α-chemokines) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) of

interleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors
, of which seven have been discovered to date, designated CXCR1-7.

C chemokines

The third group of chemokines is known as the C chemokines (or γ chemokines), and is unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream. Two chemokines have been described for this subgroup and are called XCL1 (

lymphotactin
-β).

CX3C chemokines

A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX3C chemokine (or d-chemokines). The only CX3C chemokine discovered to date is called

adhesion molecule
.

Receptors

hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conserved cysteine residue that allow formation of a disulfide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity.[14]

Signal transduction

Chemokine receptors associate with G-proteins to transmit

Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor.[14]

Infection control

The discovery that the β chemokines

RANTES, MIP (macrophage inflammatory proteins) 1α and 1β (now known as CCL5, CCL3 and CCL4 respectively) suppress HIV-1 provided the initial connection and indicated that these molecules might control infection as part of immune responses in vivo,[15] and that sustained delivery of such inhibitors have the capacity of long-term infection control.[16] The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection.[17]

See also

  • Paracrine signalling

References

External links