Abstract
The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and gp330, two members of the low density lipoprotein receptor gene family, share a multitude of cysteine-rich repeats. LRP has been shown to act as an endocytosis-mediating receptor for several ligands, including protease-antiprotease complexes and plasma lipoproteins. The former include alpha 2-macroglobulin-protease complexes and plasminogen activator inhibitor-activator complexes. The latter include chylomicron remnant-like particles designated beta-very low density lipoproteins (beta-VLDL) complexed with apoprotein E or lipoprotein lipase. The binding specificity of gp330 is unknown. In the current studies we show that gp330 from rat kidney membranes binds several of these ligands on nitrocellulose blots. We also show that both LRP and gp330 bind an additional ligand, bovine lactoferrin, which is known to inhibit the hepatic clearance of chylomicron remnants. Lactoferrin blocked the LRP-dependent stimulation of cholesteryl ester synthesis in cultured human fibroblasts elicited by apoprotein E-beta-VLDL or lipoprotein lipase-beta-VLDL complexes. Cross-competition experiments in fibroblasts showed that the multiple ligands recognize at least three distinct, but partially overlapping sites on the LRP molecule. Binding of all ligands to LRP and gp330 was inhibited by the 39-kDa protein, which co-purifies with the two receptors, suggesting that the 39-kDa protein is a universal regulator of ligand binding to both receptors. The correlation of the inhibitory effects of lactoferrin in vivo and in vitro support the notion that LRP functions as a chylomicron remnant receptor in liver. LRP and gp330 share a multiplicity of binding sites, and both may function as endocytosis-mediating receptors for a large number of ligands in different organs.
Highlights
Low Density Lipoprotein Receptor-relatedProtein and a 3 3 0 Bind Similar Ligands, Including Plasminogen Activator-Inhibitor Complexes and Lactoferrina, n Inhibitor of Chylomicron Remnant Clearance*
BcpdpmToilerhnaeomsesdritmgepiinlanlniaegsnacxtetolteeuegscdddrpeoiewen&nmcacipivatzlfhucl-eiemctdrxiiyaevtaepyacscolotohrfaopwoygnrrglpodoild3tnomeep3hbinlin0iucasbrsliiioistmEtnoynou-rarnlpr-likelirpaipmnocopoottponiepwvrpaaroaronnstotet.etocte-iIeorlinniinmsknclsepiot(.plh8meTpa-exsahVpeerelst.LeciTxacDufoenlhrLesrdres.-)enttcrrTyeeohppqTmeeeuhpaipreftleeoreodldmrotwefteshoinenridqtss-leutinyfgdeaspanimifnectfydeeilrsrybel.iipipAnn(eo2dlaltp,iohtnrs3feoga)t..nentdIihuntmec(bpooLenrnDorettaLaeic)ninln’dussrseaotbecrnrireenapdnotcogflCuretmsahits2ere+etrnhe,twoesfghporisfrcoeohwvttheotinehsstudies we show that gp[330] from rat kidney mem- factor repeats, the latter separated by a cysteine-poor spacer branes binds severalof these ligandson nitrocellulose that contains five copies of the YWTD sequence
We show that both LRP and gp330bind an receptor binds plasma lipoproteins that contain apoB-100 or additional ligand, bovine lactoferrin, whichis known apoE, and it is responsible for the removal of most intermeto inhibit the hepatic clearance of chylomicron rem- diate density lipoproteins and LDL from plasma
Summary
This fusion protein, which contains the entire coding 2 ). PAI-1 complex,the stripswere preinthe emergence of free cholesterol from the lysosome (34).Fig. 7A shows that imipramine abolished the stimulation of cholesteryl ester synthesis that was achieved by apoE/P-VLDL and LPL/P-VLDL. Terol plus cholesterol (Fig. 7 8 ) , nor did it inhibit [‘4C]oleate incorporation into [14C]triglycerides(data not shown) These data add further confirmation to theidea that LPL/P-VLDL required uptake and degradation in lysosomes in order to stimulate cholesteryl ester synthesis. +Lp Lipase it delivers P-VLDL to lysosomes where the cholesteryl esters of the lipoprotein are hydrolyzed and made available for cellular cholesteryl ester synthesis
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