Attachment of C-terminus of SDF-1 enhances the biological activity of its N-terminal peptide.

The N-terminus of stromal cell-derived factor 1 (SDF-1) is known to be a critical site for CXCR4 receptor binding and signaling. However, the functional role of other regions, in particular the C-terminal helix of SDF-1, has yet to be defined. In this study, we designed and synthesized a peptide model of SDF-1 containing its N- and C-terminal regions. The attachment of the C-terminus of SDF-1, which by itself had no activity in receptor binding and signaling, dramatically increased the effect of the N-terminal fragment in inducing chemotaxis and intracellular Ca(2+) influx in sup T1 cells compared with the peptide containing only the N-terminal sequence. The enhancement in activity was not due to the increase in receptor affinity as the N,C-terminal peptide did not show higher CXCR4 binding than the N-terminal peptide. On the other hand, the intracellular Ca(2+) influx activated by the N,C-terminal peptide, but not the N-terminal peptide, was completely abolished by the addition of heparin, suggesting that the C-terminal fragment of the peptide binds glycosaminoglycans (GAGs) and exerts an effect to modulate biological activity. These data raise the possibility that the C-terminus in native SDF-1 is one of interaction sites with GAGs and may be associated with biological function of SDF-1. Furthermore, this study demonstrates an approach for the design of novel agonists or antagonists of other chemokine receptors that possess enhanced biological activity. Copyright 1999 Academic Press.