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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1284-1291.
Prepublished online as a Blood First Edition Paper on October 18, 2005; DOI 10.1182/blood-2005-08-3112.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
A310 helical turn is essential for the proliferation-inhibiting properties of macrophage inflammatory protein-1 alpha (CCL3)
Katrin Ottersbach,
John Mclean,
Neil W. Isaacs, and
Gerard J. Graham
From the Division of Immunology, Infection and Inflammation; and Department of Chemistry, University of Glasgow, Scotland, United Kingdom.
Despite possessing marked structural similarities, the chemokines macrophage inflammatory protein-1 (MIP-1 ; CCL3) and RANTES (CCL5) display differential activity in hematopoietic progenitor-cell-inhibitory assays, with MIP-1 being active and RANTES inactive in this context. We have sought to identify the key structural determinants of this property of MIP-1 . This has involved constructing MIP-1 /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-1 and further domain swap analysis has narrowed this down to the 310 helical turn preceding the first -strand in MIP-1 . 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-1 in inhibition of hematopoietic progenitor-cell proliferation and regulation of leukocyte migration.

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