The carboxyl-terminal domain of closely related endotoxin-binding proteins determines the target of protein-lipopolysaccharide complexes.

Abstract The bactericidal/permeability increasing (BPI) and lipopolysaccharide (LPS)-binding (LBP) proteins are closely related two-domain proteins in which LPS binding is mediated by the NH2-terminal domain. To further define the role of the COOH-terminal domain of these proteins in delivery of LPS to specific host acceptors, we have compared interactions of LBP, BPI, LBPN-BPIC (NH2-terminal domain of LBP, COOH-terminal domain of BPI), and BPIN-LBPC with purified 3H-LPS and, subsequently, with purified leukocytes and soluble (s)CD14. The COOH-terminal domain of LBP promotes delivery of LPS to CD14 on both polymorphonuclear leukocytes and monocytes resulting in cell activation. In the presence of Ca2+ and Mg2+, LBP and BPI each promote aggregation of LPS to protein-LPS aggregates of increased size (apparent M r > 20 × 106 Da), but only LPS associated with LBP and BPIN-LBPC is disaggregated in the presence of CD14. BPI and LBPN-BPIC promote apparently CD14-independent LPS association to monocytes without cell activation. These findings demonstrate that the carboxyl-terminal domain of these closely related endotoxin-binding proteins dictates the route and host responses to complexes they form with endotoxin.