The Chemokine Superfamily

There are currently 18 known chemokine receptors and 45 ligands although these numbers do not include alternative splice variants, which exist for both the ligands (Baird et al, 1999) and receptors (Gupta et al. 

In addition to determining structures, a large number of studies have defined receptor-binding epitopes on chemokines. The seminal structure-function studies were done on IL-8/GGL8. By generating synthetic 

In the case of two chemokines with G-terminal tails (e.g., lymphotactin/ XGLl and M1G/GXGL9), truncation studies have shown that these domains are also critical for function (Glark-Lewis et al, 2003 Hedrick et al, 1997). Interestingly, like the N-terminal triggering domain, in XGLl, the G-terminal tail is unstructured. 

The classical view of GPCR signal transduction involves activation of trimeric G-proteins, and in the case of chemokine receptors, Gai is key, as indicated by their sensitivity to pertussis toxin. However, evolving theories of dimerization-induced signal transduction add an intermediate 

Sequence analysis and molecular modeling has also been used to identify potential amino acids involved in the dimerization of CCR5 (Hernanz-Falcon et al, 2004). In this study, a large region of TMl and TM4 was predicted to comprise the dimer interface with 152 and VI50 making particularly important contacts (Fig. 7). To test this hypothesis, a double 

---

Wetzel MA, Steele AD, Eisenstein TK, Adler MW, Henderson EE, Rogers TJ (2000) Mu-opioid induction of monocyte chemoattractant protein-1, RANTES, and IFN-gamma-inducible protein-10 expression in human peripheral blood mononuclear cells. J Immunol 165 6519-6524 Widmer U, Manogue KR, Cerami A, Sherry B (1993) Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. J Immunol 150 4996-5012 Ye RD (2001) Regulation of nuclear factor kappaB activation by G-protein-coupled receptors. [Review] [136 refs]. J Leukoc Biol 70 839-848... 

Based on the presence or absence of conserved cysteine residues within their primary sequence, the chemokine superfamily can be separated into four distinct subfamilies called the C-X-C (or a), the C-C (or (3), the C, or the C-X-X-X-C subfamilies (1-2). Chemokines share many other similarities including their high basic nature as well as their ability to bind heparin through heparinbinding domains. These molecules exhibit sequence identity at the amino acid level between 24 and 80%. Historically, the chemokine subfamilies... 

Houshmand, P., and Zlotnik, A. (2003). Therapeutic applications in the chemokine superfamily. Curr. Opin. Chem. Biol. 7, 457-460. 

Interestingly, there is a certain degree of promiscuity in the chemokine superfamily with many ligands binding different receptors or vice versa. So-called cluster chemokines representing chemotactic proteins which share a distinct chromosomal location are likely to bind the same receptors. However, noncluster or microcluster chemokines are ligands which demonstrate a unique chromosomal location and tend to present a restricted or even specific chemokine receptor interaction [23]. 

IV. Genomic Evolution of the Chemokine Superfamily Functional Significance... 

Zlomik, A., Yoshie, O. (2012). The chemokine superfamily revisited. Immunity, 36(5),... 

MGSA/GRO Is a Member of the Chemokine Superfamily of Chemotactic Cytokines... 

Hosaka, S., Akahoshi, T., Wada, C., and Kondo, H. (1994). Expression of the chemokine superfamily in rheumatoid arthritis. Clin. Exp. Immunol. 97, 451-457. 

---