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

TitleA310 helical turn is essential for the proliferation-inhibiting properties of macrophage inflammatory protein-1 alpha (CCL3).
Publication TypeJournal Article
Year of Publication2006
AuthorsOttersbach K, McLean J, Isaacs NW, Graham GJ
Date Published2006 Feb 15
KeywordsAmino 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.

Alternate JournalBlood
PubMed ID16234357
Grant ListG0800784 / / Medical Research Council / United Kingdom
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