A310 helical turn is essential for the proliferation-inhibiting properties of macrophage inflammatory protein-1 alpha (CCL3)

Abstract

Despite possessing marked structural similarities, the chemokines macrophage inflammatory protein-1α (MIP-1α; CCL3) and RANTES (CCL5) display differential activity in hematopoietic progenitor-cell-inhibitory assays, with MIP-1α being active and RANTES inactive in this context. We have sought to identify the key structural determinants of this property of MIP-1α. This has involved constructing MIP-1α/RANTES chimeras by swapping structural domains between the 2 proteins. Results indicate that, in contrast to other chemokine functions, neither the N nor the C termini are key determinants of inhibitory activity. The motif that appears to be most important for this activity lies between the second and fourth cysteines of MIP-1α and further domain swap analysis has narrowed this down to the 310 helical turn preceding the first β-strand in MIP-1α. More detailed analysis has highlighted the role played by a specific dipeptide motif in the proliferation-inhibitory activity of chemokines. The involvement of the 310 helical-turn motif in chemokine function is unprecedented and this study therefore identifies a novel, functionally essential motif within chemokines. In addition, this study further attests to the alternative mechanisms of action used by MIP-1α in inhibition of hematopoietic progenitor-cell proliferation and regulation of leukocyte migration.