|Title||A310 helical turn is essential for the proliferation-inhibiting properties of macrophage inflammatory protein-1 alpha (CCL3).|
|Publication Type||Journal Article|
|Year of Publication||2006|
|Authors||Ottersbach K, McLean J, Isaacs NW, Graham GJ|
|Date Published||2006 Feb 15|
|Keywords||Amino Acid Sequence, Animals, Base Sequence, Cell Division, Chemokine CCL3, Chemokine CCL4, Chemokine CCL5, Chemokines, CC, Colony-Forming Units Assay, DNA Primers, Hematopoietic Stem Cells, Humans, Macrophage Inflammatory Proteins, Mice, Molecular Sequence Data, Protein Structure, Secondary, Recombinant Proteins, Sequence Alignment, Sequence Homology, Amino Acid|
Despite possessing marked structural similarities, the chemokines macrophage inflammatory protein-1alpha (MIP-1alpha; CCL3) and RANTES (CCL5) display differential activity in hematopoietic progenitor-cell-inhibitory assays, with MIP-1alpha being active and RANTES inactive in this context. We have sought to identify the key structural determinants of this property of MIP-1alpha. This has involved constructing MIP-1alpha/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-1alpha and further domain swap analysis has narrowed this down to the 3 10 helical turn preceding the first beta-strand in MIP-1alpha. More detailed analysis has highlighted the role played by a specific dipeptide motif in the proliferation-inhibitory activity of chemokines. The involvement of the 3 10 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-1alpha in inhibition of hematopoietic progenitor-cell proliferation and regulation of leukocyte migration.
|Grant List||G0800784 / / Medical Research Council / United Kingdom|