POSSIBLE FUNCTIONAL INTERACTIONS OF APOLIPOPROTEIN B-100 SEGMENTS THAT ASSOCIATE WITH CELL PROTEOGLYCANS AND THE APOB E RECEPTOR/

The interaction of apoE lipoproteins with cells appears to be mediated by an association with basic sequences of proteoglycans and the apoB/ E receptor. ApoB-100 has basic sequences, homologous with those of apo E, that form part of the apoB/E receptor-binding domain. These sequenc es of apoB-100 also interact with proteoglycans. We investigated wheth er such segments, in analogy with apoE, could act cooperatively on LDL interactions with proteoglycans and the receptor. As a model we used the two most basic regions of apoB-100, 3147 through 3157 and 3359 thr ough 3367, connected by three glycines (3145-3157-GGG-3359-3367). Such segments may be proximal in LDL by the presence of a disulfide bridge between Cys(3167) and Cys(3297). The apoB heterodimer but not the sep arated monomers inhibited I-125-LDL degradation in fibroblasts and THP -1 cells by 50% at approximate to 11 mu mol/L. The heterodimer affinit y with arterial proteoglycans was closer to that of LDL and higher tha n that of the individual peptides. The heterodimer appears to bind spe cifically to THP-1 cells, with a K-d of 6.2X10(-8) mol/L and a B-max o f 1.3X10(6) molecules/cell. Monoclonal antibody C-7, which recognizes the apoB receptor, inhibited the binding to cells. Treatment of fibrob lasts with chondroitinase ABC or chlorate decreased I-125-LDL degradat ion markedly. Hydrolysis of pericellular proteoglycans of fibroblasts by chondroitinases reduced mostly the low-affinity, high-capacity comp onent of LDL binding. This compartment appears to hold 70% of the cell -associated LDL when internalization is inhibited at 4 degrees C. Ther efore, cell-surface chondroitin sulfate/dermatan sulfate proteoglycans appear to modulate binding and receptor-mediated internalization of L DL. This may be caused, at least in part, by the association of proteo glycans with the apoB-100 segments 3145 through 3157 and 3359 through 3367.