Chemokines oligomerization

Key Words Chemokines oligomerization GPCR GAGs heparin crystallography NMR structure. 

While the tertiary structures are similar among all chemokines characterized to date, and some are monomeric in solution, many chemokines oligomerize, forming... 

Suzuki S, Chuang LE, Yau P, Doi RH, Chuang RY (2002b) Interactions of opioid and chemokine receptors oligomerization of mu, kappa, and delta with CCR5 on immune cells. Exp Cell Res 280 192-200... 

The oligomeric structures of chemokines vary. CXCL8 (IL-8), the prototypical CXC chemokine, is dimeric in solution (26) and in its crystalline form (due to twofold crystallographic symmetry) (27). The three-stranded P-sheet of each subunit joins to form a six-stranded P-sheet (Figure IB). The two C-terminal... 

Fig. 1. Oligomerization of CXC chemokines. (A) Monomeric form of CXCL8 (IL-8) with disulfide bridges shown as black sticks. (B) Dimeric form of CXCL8 showing six-stranded P-sheet. (C) Tetrameric form of CXCL10 (IP-10).

Fig. 2. Oligomerization of CC chemokines. (A) Dimeric form of CCL4 (MIP-ip). (B) Tetrameric form of CCL2 (MCP-1) highlighting both CC dimerization (left) and CXC dimerization (right). (C) CCL20 forms liver and activation regulated chemokine (LARC) a CXC dimer.

Swaminathan GJ, Holloway DE, Colvin RA, et al. Crystal structures of oligomeric forms of the IP-10/CXCL10 chemokine. Structure 2003 11 521-32. 

Hoogewerf AJ, Kuschert GS, Proudfoot AE, et al. Glycosaminoglycans mediate cell surface oligomerization of chemokines. Biochemistry 1997 36 13570-8. 

Proudfoot AE, Handel TM, Johnson Z, et al. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc Natl Acad Sci U S A 2003 100 1885-90. 

Interferon-7-inducible protein 10 kDa (IP-IO/GXGLIO) is a chemokine that in solution, exists in equilibrium between monomer and dimer. A solution structure of a monomeric variant has been solved by NMR (Booth et al, 2002). However, like MGP-1, it has also been crystallized in different space groups, revealing tetrameric oligomerization states (Swaminathan et al, 2003). One of the forms is similar to the PF4 and MGP-1 tetramers. The other two tetramers form a novel twelve-stranded /3-sheet containing structure (Fig. 9), which the authors postulate could represent structures induced by binding of different GAGs. 

Fig. 9. Ribbon structures of the three IP-IO/CXCLIO tetramers. Two orthogonal views are shovm for each. The M-form is similar to the PF4/CXCL8 and MCP-1/CCL2 structures that contain elements of CXC and CC dimers. The T and H forms contain a novel 12-stranded / -sheet. Reprinted from Structure with copyright permission from Elsevier. Swaminathan, G. et al. (2003). Crystal structures of oligomeric forms of the IP-lO/CXCLlO chemokine. Structure 11, 521-532. (See Color Insert.)...

Another remarkable aspect of this protein is its ability to bind many different chemokines across all four families with nanomolar affinities (van Berkel et al, 2000). While no common chemokine sequence motifs have been identified thus far, the promiscuity of M3 has been partly attributed to structural plasticity as a consequence of its oligomeric framework, which can undergo structural rearrangements, and the use of flexible loops as primary contact regions. Future studies of additional M3 chemokine complexes will undoubtedly provide further insight into the brilliant design of this highly evolved viral stealth weapon. 

Johnson, Z., Kosco-Vibois, M., Herren, S., Cirillo, R., Muzio, V., Smailbegovis, A., Rose, M., Lever, R., Page, C., Wells, T., and Proudfoot, A. E. I. (2004). Interference with heparin binding and oligomerization creates a novel antiinflammatory strategy targeting the chemokine system. Proc. Natl. Acad. Sci. USA, submitted. 

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