Chemokines and Glycosaminoglycans

Previously, the structure of MGP-1 /GGL2 was solved by NMR and subsequently by X-ray crystallography using the NMR structure as a starting model for molecular replacement (Lubkowski et al, 1997). As described in Section II.B, the solution structure revealed a dimer similar to dimerization motifs observed for other GC chemokines. In the case of the X-ray structure, two different crystal forms were isolated from the same droplet. One form contained a dimer similar to the solution structure (Fig. 2B), while the other form contained a tetramer as shown in Fig. 8. In the tetramer, there is a primary CC dimer interface that consists of the 

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. 

While the structural biology of chemokine GAG interactions is only beginning to emerge, a quote from a review on heparan sulfate glycos-aminoglycans (HSGAGs) adds perspective on how diverse these interactions may be, compared to other biopolymers (Shriver et al, 2002)  

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Johnson Z, Proudfoot AE, Handel TM (2005) Interaction of chemokines and glycosaminoglycans a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Rev 16 625-636 Jones G, Power C (2006) Regulation of neural cell survival by HIV-1 infection. Neurobiol Dis 21 1-17... 

The Role of Chemokine and Glycosaminoglycan Interaction in Chemokine-Mediated Migration In Vitro and In Vivo... 

Kuschert, G.S., F. Coulin, C.A. Power, A.E. Proudfoot, R.E. Hubbard, A.J. Hoogewerf, and T.N. Wells. 1999. Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry 38 12959-12968. 

Witt, D. P. and Lander, A. D. (1994) Differential binding of chemokines to glycosaminoglycan subpopulations. Curr. Biol. 4, 394-400. 

Finally, posttranslational modification of chemokines is another level of complexity when trying to understand the effects of chemokines in vivo. Recruited leukocytes and the inflamed tissue are a rich source of different enzymes that alter the structure of chemokines, changing their interaction with receptors and glycosaminoglycans and modifying their actions. Proteolysis, glycosylation, citrullination, and nitration are examples of how chemokines can be modified (Mortier et al., 2012). For instance, CD26 (also known as dipeptidylpeptidase 4) is a protease that can remove the first two amino acids from a protein that possesses a proHne or alanine in the... 

Structural Aspects of Chemokines and their Interactions with Receptors and Glycosaminoglycans... 

Webb, L.M., Smith, V.P., and Alcami, A. (2004) The gammaherpesvirus chemokine binding protein can inhibit the interaction of chemokines with glycosaminoglycans. The FASEB Journal, 18, 571-573. 

Biology of CC Chemokines and Their Receptors X. CHEMOKINE BINDING TO GLYCOSAMINOGLYCANS... 

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