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 cr itical site for CXCR4 receptor binding and signaling. However, the function al 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 mod el 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 a nd signaling, dramatically increased the effect of the N-terminal fragment in inducing chemotaxis and intracellular Ca2+ influx in sup T1 cells compar ed with the peptide containing only the N-terminal sequence. The enhancemen t in activity was not due to the increase in receptor affinity as the N,C-t erminal peptide did not show higher CXCR4 binding than the N-terminal pepti de. On the other hand, the intracellular Ca2+ influx activated by the N,C-t erminal peptide, but not the N-terminal peptide, was completely abolished b y the addition of heparin, suggesting that the C-terminal fragment of the p eptide binds glycosaminoglycans (GAGs) and exerts an effect to modulate bio logical activity. These data raise the possibility that the C-terminus in n ative SDF-1 is one of interaction sites with GAGs and may be associated wit h biological function of SDF-1. Furthermore, this study demonstrates an app roach for the design of novel agonists or antagonists of other chemokine re ceptors that possess enhanced biological activity. (C) 1999 Academic Press.