SCY

Intercrine alpha family (small cytokine C-X-C) (chemokine CXC).

• SMART accession number: SM00199
• Description: Family of cytokines involved in cell-specific chemotaxis, mediation of cell growth, and the inflammatory response.
• Interpro abstract (IPR001811):

  Many low-molecular weight factors secreted by cells including fibroblasts, macrophages and endothelial cells, in response to a variety of stimuli such as growth factors, interferons, viral transformation and bacterial products, are structurally related [(PUBMED:1910690), (PUBMED:2149646), (PUBMED:2687068)]. Most members of this family of proteins seem to have mitogenic, chemotactic or inflammatory activities. These small cytokines are also called intercrines or chemokines. They are cationic proteins of 70 to 100 amino acid residues that share four conserved cysteine residues involved in two disulphide bonds, as shown in the following schematic representation:

                               +------------------------------------+
                               |                                    |
       xxxxxxxxxxxxxxxxxxxxxxCxCxxxxxxxxxxxxxxxxxxxxxxxCxxxxxxxxxxxxCxxxxx
                             |                         |
                             +-------------------------+
  'C': conserved cysteine involved in a disulphide bond.
  

  Chemokines can be sorted into main groups based on the spacing of the two amino-terminal cysteines. In the first group (see IPR001089), the two cysteines are separated by a single residue (C-x-C), while in the second group (see IPR000827), they are adjacent (C-C).

• GO process: immune response (GO:0006955)
• GO component: extracellular region (GO:0005576)
• GO function: chemokine activity (GO:0008009)

There are 1028 SCY domains in 1028 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Baggiolini M, Dewald B, Moser B
• Human chemokines: an update.
• Annu Rev Immunol. 1997; 15: 675-705

Interleukin 8, the first chemokine to be characterized, was discovered nearly ten years ago. Today, more than 30 human chemokines are known. They are often upregulated in inflammation and act mainly on leukocytes inducing migration and release responses. The present review deals largely with the new developments of the last three years. Several structural studies have shown that most chemokines form dimers. The dimers, however, dissociate upon dilution, and the monomers constitute the biologically active form. Chemokine activities are mediated by seven-transmembrane-domain, G protein coupled receptors, five of which were discovered in the past three years. The primary receptor-binding domain of all chemokines is near the NH2 terminus, and antagonists can be obtained by truncation or substitutions in this region. Major progress has been made in the understanding of chemokine actions on T lymphocytes that respond to several CC chemokines but also to IP10 and Mig, two CXC chemokines that selectively attract T cells via a novel receptor. Effects of chemokines on angiogenesis and tumor growth have been reported, but the data are still contradictory and the mechanisms unknown. Of considerable interest is the recent discovery that some chemokines function as HIV-suppressive factors by interacting with chemokine receptors which, together with CD4, were recognized as the binding sites for HIV-1.

• Neville LF, Mathiak G, Bagasra O
• The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily.
• Cytokine Growth Factor Rev. 1997; 8: 207-19

Interferon-gamma inducible protein 10 kD (IP-10) is a highly inducible, primary response gene that belongs to the C-X-C chemokine superfamily. Despite the original cloning of IP-10 in 1985, its biological functions are still unclear although accumulating reports indicate that it is a pleiotropic molecule capable of eliciting potent biological effects, including stimulation of monocytes, natural killer and T-cell migration, regulation of T-cell and bone marrow progenitor maturation, modulation of adhesion molecule expression as well as inhibition of angiogenesis. More interest is now likely to be focused on IP-10 due to the recent cloning of an IP-10 receptor. This paper aims to highlight our current knowledge of IP-10 and its homologues as well as defining its likely involvement in regulating fibroproliferation following inflammatory lung injury.

• Baggiolini M, Dewald B, Moser B
• Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines.
• Adv Immunol. 1994; 55: 97-179

• Baggiolini M, Clark-Lewis I
• Interleukin-8, a chemotactic and inflammatory cytokine.
• FEBS Lett. 1992; 307: 97-101

Interleukin-8 (IL-8) belongs to a family of small, structurally related cytokines similar to platelet factor 4. It is produced by phagocytes and mesenchymal cells exposed to inflammatory stimuli (e.g., interleukin-1 or tumor necrosis factor) and activates neutrophils inducing chemotaxis, exocytosis and the respiratory burst. In vivo, IL-8 elicits a massive neutrophil accumulation at the site of injection. Five neutrophil-activating cytokines similar to IL-8 in structure and function have been identified recently. IL-8 and the related cytokines are produced in several tissues upon infection, inflammation, ischemia, trauma etc., and are thought to be the main cause of local neutrophil accumulation.

• Clore GM, Appella E, Yamada M, Matsushima K, Gronenborn AM
• Three-dimensional structure of interleukin 8 in solution.
• Biochemistry. 1990; 29: 1689-96

The solution structure of the interleukin 8 (IL-8) dimer has been solved by nuclear magnetic resonance (NMR) spectroscopy and hybrid distance geometry-dynamical simulated annealing calculations. The structure determination is based on a total of 1880 experimental distance restraints (of which 82 are intersubunit) and 362 torsion angle restraints (comprising phi, psi, and chi 1 torsion angles). A total of 30 simulated annealing structures were calculated, and the atomic rms distribution about the mean coordinate positions (excluding residues 1-5 of each subunit) is 0.41 +/- 0.08 A for the backbone atoms and 0.90 +/- 0.08 A for all atoms. The three-dimensional solution structure of the IL-8 dimer reveals a structural motif in which two symmetry-related antiparallel alpha-helices, approximately 24 A long and separated by about 14 A, lie on top of a six-stranded antiparallel beta-sheet platform derived from two three-stranded Greek keys, one from each monomer unit. The general architecture is similar to that of the alpha 1/alpha 2 domains of the human class I histocompatibility antigen HLA-A2. It is suggested that the two alpha-helices form the binding site for the cellular receptor and that the specificity of IL-8, as well as that of a number of related proteins involved in cell-specific chemotaxis, mediation of cell growth, and the inflammatory response, is achieved by the distinct distribution of charged and polar residues at the surface of the helices.

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
79.37	map04060	Cytokine-cytokine receptor interaction
14.68	map04620	Toll-like receptor signaling pathway
3.97	map04670	Leukocyte transendothelial migration
1.98	map05219	Bladder cancer

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with SCY domain which could be assigned to a KEGG orthologous group, and not all proteins containing SCY domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of SCY domains in PDB

PDB code	Title
1a15	Sdf-1alpha
1b2t	Solution structure of the cx3c chemokine domain of fractalkine
1b3a	Total chemical synthesis and high-resolution crystal structure of the potent anti-hiv protein aop-rantes
1b50	Nmr structure of human mip-1a d26a, 10 structures
1b53	Nmr structure of human mip-1a d26a, minimized average structure
1bo0	Monocyte chemoattractant protein-3, nmr, minimized average structure
1cm9	Crystal structure of viral macrophage inflammatory protein- ii
1dok	Monocyte chemoattractant protein 1, p-form
1dol	Monocyte chemoattractant protein 1, i-form
1dom	Solution structure of the monocyte chemoattractant protein- dimer using heteronuclear, nmr, minimized average structure
1don	Solution structure of the monocyte chemoattractant protein- dimer using heteronuclear, nmr, 20 structures
1eig	Solution structure of the human chemokine eotaxin-2
1eih	Solution structure of the human chemokine eotaxin-2
1el0	Solution structure of the human cc chemokine, i-309
1eot	Solution nmr structure of eotaxin, minimized average structure
1eqt	Met-rantes
1esr	Crystal structure of human monocyte chemotactic protein-2
1f2l	Crystal structure of chemokine domain of fractalkine
1f9p	Crystal structure of connective tissue activating peptide- iii(ctap-iii) complexed with polyvinylsulfonic acid
1f9q	Crystal structure of platelet factor 4
1f9r	Crystal structure of platelet factor 4 mutant 1
1f9s	Crystal structure of platelet factor 4 mutant 2
1g2s	Solution structure of eotaxin-3
1g2t	Solution structure of eotaxin-3
1g91	Solution structure of myeloid progenitor inhibitory factor- (mpif-1)
1ha6	Nmr solution structure of murine ccl20/mip-3a chemokine
1hfg	Nmr solution structure of vmip-ii 1-71 from kaposi's sarcoma-associated herpesvirus (minimized average structure).
1hfn	Nmr solution structures of vmip-ii 1-71 from kaposi's sarcoma-associated herpesvirus.
1hhv	Solution structure of virus chemokine vmip-ii
1hrj	Human rantes, nmr, 13 structures
1hum	Solution structure of the chemokine hmip-1beta(slash)act-2 by multi-dimensional nmr: a novel chemokine dimer
1hun	Solution structure of the chemokine hmip-1beta(slash)act-2 by multi-dimensional nmr: a novel chemokine dimer
1icw	Interleukin-8, mutant with glu 38 replaced by cys and cys replaced by ala
1ikl	Nmr study of monomeric human interleukin-8 (minimized average structure)
1ikm	Nmr study of monomeric human interleukin-8 (30 structures)
1il8	Three-dimensional structure of interleukin 8 in solution
1ilp	Cxcr-1 n-terminal peptide bound to interleukin-8
1ilq	Cxcr-1 n-terminal peptide bound to interleukin-8 (minimized mean)
1j8i	Solution structure of human lymphotactin
1j9o	Solution structure of human lymphotactin
1je4	Solution structure of the monomeric variant of the chemokine mip-1beta
1lv9	Cxcr3 binding chemokine ip-10/cxcl10
1m8a	Human mip-3alpha/ccl20
1mgs	The solution structure of melanoma growth stimulating activity
1mi2	Solution structure of murine macrophage inflammatory protein-2, nmr, 20 structures
1ml0	Viral chemokine binding protein m3 from murine gammaherpesvirus68 in complex with the p8a variant of cc- chemokine mcp-1
1msg	Solution structure of gro(slash)melanoma growth stimulatory activity determined by 1h nmr spectroscopy
1msh	Solution structure of gro(slash)melanoma growth stimulatory activity determined by 1h nmr spectroscopy
1nap	The crystal structure of recombinant human neutrophil- activating peptide-2 (m6l) at 1.9-angstroms resolution
1ncv	Determination cc-chemokine mcp-3, nmr, 7 structures
1nr2	High resolution crystal structures of thymus and activation- regulated chemokine
1nr4	High resolution crystal structures of thymus and activation- regulated chemokine
1o7y	Crystal structure of ip-10 m-form
1o7z	Crystal structure of ip-10 t-form
1o80	Crystal structure of ip-10 h-form
1pfm	Pf4-m2 chimeric mutant with the first 10 n-terminal residues of r-pf4 replaced by the n-terminal residues of the il8 sequence. models 1-15 of a 27-model set.
1pfn	Pf4-m2 chimeric mutant with the first 10 n-terminal residues of r-pf4 replaced by the n-terminal residues of the il8 sequence. models 16-27 of a 27-model set.
1plf	The three-dimensional structure of bovine platelet factor 4 at 3.0 angstroms resolution
1qe6	Interleukin-8 with an added disulfide between residues 5 and 33 (l5c/h33c)
1qg7	Stroma cell-derived factor-1alpha (sdf-1alpha)
1qnk	Truncated human grob[5-73], nmr, 20 structures
1rhp	Crystal structure of recombinant human platelet factor 4
1rjt	Nmr structure of cxc chemokine cxcl11/itac
1rod	Chimeric protein of interleukin 8 and human melanoma growth stimulating activity protein, nmr
1rtn	Proton nmr assignments and solution conformation of rantes, a chemokine of the cc type
1rto	Proton nmr assignments and solution conformation of rantes, a chemokine of the cc type
1sdf	Solution structure of stromal cell-derived factor-1 (sdf-1), nmr, minimized average structure
1tvx	Neutrophil activating peptide-2 variant form m6l with five additional amino terminal residues (dsdly)
1u4l	Human rantes complexed to heparin-derived disaccharide i-s
1u4m	Human rantes complexed to heparin-derived disaccharide iii-s
1u4p	Crystal structure of human rantes mutant k45e
1u4r	Crystal structure of human rantes mutant 44-aana-47
1vmc	Stroma cell-derived factor-1alpha (sdf-1alpha)
1vmp	Structure of the anti-hiv chemokine vmip-ii
1zxt	Crystal structure of a viral chemokine
2bdn	Crystal structure of human mcp-1 bound to a blocking antibody, 11k2
2d1h	Crystal structure of st1889 protein from thermoacidophilic archaeon sulfolobus tokodaii
2eot	Solution structure of eotaxin, an ensemble of 32 nmr solution structures
2ffk	Solution structure of the complex between poxvirus-encoded cc chemokine inhibitor vcci and human mip-1beta, minimized average structure
2fht	Crystal structure of viral macrophage inflammatory protein- ii
2fin	Solution structure of the complex between poxvirus-encoded cc chemokine inhibitor vcci and human mip-1beta, ensemble structure
2fj2	Crystal structure of viral macrophage inflammatory protein- ii
2hcc	Solution structure of the human chemokine hcc-2, nmr, 30 structures
2hci	Structure of human mip-3a chemokine
2hdl	Solution structure of brak/cxcl14
2hdm	Solution structure of v21c/v59c lymphotactin/xcl1
2il8	Three-dimensional structure of interleukin 8 in solution
2j7z	Crystal structure of recombinant human stromal cell-derived factor-1alpha
2jp1	Solution structure of the alternative conformation of xcl1/lymphotactin
2jyo	Nmr solution structure of human mip-3alpha/ccl20
2k01	Structure of a locked sdf1 dimer
2k03	Structure of sdf1 in complex with the cxcr4 n-terminus containing a sulfotyrosine at postition 21
2k04	Structure of sdf1 in complex with the cxcr4 n-terminus containing no sulfotyrosines
2k05	Structure of sdf1 in complex with the cxcr4 n-terminus containing sulfotyrosines at postitions 7, 12 and 21
2kec	Structure of sdf-1/cxcl12
2ked	Structure of sdf-1/cxcl12
2kee	Structure of sdf-1/cxcl12
2nwg	Structure of cxcl12:heparin disaccharide complex
2nyz	Viral chemokine binding protein m3 from murine gammaherpesvirus68 in complex with the c- chemokine xcl1
2nz1	Viral chemokine binding protein m3 from murine gammaherpesvirus68 in complex with the cc-chemokine ccl2/mcp-1
2q8r	Structural and functional characterization of cc chemokine ccl14
2q8t	Crystal structure of the cc chemokine ccl14
2r3z	Crystal structure of mouse ip-10
2ra4	Crystal structure of human monocyte chemoattractant protein (mcp-4/ccl13)
2sdf	Solution nmr structure of stromal cell-derived factor-1 (sdf-1), 30 structures
2vxw	Structural and functional studies of the potent anti-hiv chemokine variant p2-rantes
3ifd	Human synthetic monocyte chemoattractant protein 1 (mcp-1)
3il8	Crystal structure of interleukin 8: symbiosis of nmr and crystallography

Links (links to other resources describing this domain)

• BLOCKS: SMALL_CYTOKINES_CXC
• PFAM: il8
• INTERPRO: IPR001811
• PROSITE: SCY_DOMAIN