BETA(2)-GLYCOPROTEIN-1 (APOLIPOPROTEIN-H) AND BETA(2)-GLYCOPROTEIN-1-PHOSPHOLIPID COMPLEX HARBOR A RECOGNITION SITE FOR THE ENDOCYTIC RECEPTOR MEGALIN

Screening of serum by using a surface plasmon resonance analysis assay identified beta(2)-glycoprotein-I/apolipoprotein H as a plasma compon ent binding to the renal epithelial endocytic receptor megalin. A calc ium-dependent megalin-mediated beta(2)-glycoprotein-I endocytosis was subsequently demonstrated by ligand blotting of rabbit renal cortex an d uptake analysis in megalin-expressing cells. Immunohistochemical and immunoelectron microscopic examination of kidneys and the presence of high concentrations of beta(2)-glycoprotein-I in urine of mice with d isrupted megalin gene established that megalin is the renal clearance receptor for beta(2)-glycoprotein-I. A significant increase in functio nal affinity for purified megalin was observed when beta(2)-glycoprote in-I was bound to the acidic phospholipids, phosphatidylserine and car diolipin. The binding of beta(2)-glycoprotein-I and beta(2)-glycoprote in-I-phospholipid complexes to megalin was completely blocked by recep tor-associated protein. In conclusion, we have demonstrated a novel re ceptor recognition feature of beta(2)-glycoprotein-I. In addition to e xplaining the high urinary excretion of beta(2)-glycoprotein-I in pati ents with renal tubule failure, the data provide molecular evidence fo r the suggested function of beta(2)-glycoprotein-I as a linking molecu le mediating cellular recognition of phosphatidylserine-exposing parti cles.