A310 helical turn is essential for the proliferation-inhibiting properties of macrophage inflammatory protein-1 alpha (CCL3).
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.
Ottersbach
Katrin
K
Division of Immunology, Infection and Inflammation, University of Glasgow, University Avenue, Glasgow G12 8QQ, Scotland, United Kingdom.
McLean
John
J
Isaacs
Neil W
NW
Graham
Gerard J
GJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019742:Chemokines, CC / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
C483024:CCL5 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D017931:DNA Primers; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins