beta2-glycoprotein-I (apolipoprotein H) and beta2-glycoprotein-I-phospholipid complex harbor a recognition site for the endocytic receptor megalin.
Screening of serum by using a surface plasmon resonance analysis assay identified beta2-glycoprotein-I/apolipoprotein H as a plasma component binding to the renal epithelial endocytic receptor megalin. A calcium-dependent megalin-mediated beta2-glycoprotein-I endocytosis was subsequently demonstrated by ligand blotting of rabbit renal cortex and uptake analysis in megalin-expressing cells. Immunohistochemical and immunoelectron microscopic examination of kidneys and the presence of high concentrations of beta2-glycoprotein-I in urine of mice with disrupted megalin gene established that megalin is the renal clearance receptor for beta2-glycoprotein-I. A significant increase in functional affinity for purified megalin was observed when beta2-glycoprotein-I was bound to the acidic phospholipids, phosphatidylserine and cardiolipin. The binding of beta2-glycoprotein-I and beta2-glycoprotein-I- phospholipid complexes to megalin was completely blocked by receptor-associated protein. In conclusion, we have demonstrated a novel receptor recognition feature of beta2-glycoprotein-I. In addition to explaining the high urinary excretion of beta2-glycoprotein-I in patients with renal tubule failure, the data provide molecular evidence for the suggested function of beta2-glycoprotein-I as a linking molecule mediating cellular recognition of phosphatidylserine-exposing particles.
Moestrup
S K
SK
Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark.skm@biobase.dk
Schousboe
I
I
Jacobsen
C
C
Leheste
J R
JR
Christensen
E I
EI
Willnow
T E
TE
D000818:Animals; D015374:Biosensing Techniques; D001798:Blood Proteins / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002308:Cardiolipins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D006023:Glycoproteins / Q000097:blood* / Q000652:urine; D026541:Heymann Nephritis Antigenic Complex; D006801:Humans; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000502:physiology* / Q000648:ultrastructure; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism; D014407:Tumor Cells, Cultured; D053482:beta 2-Glycoprotein I
D001798:Blood Proteins; D002308:Cardiolipins; D006023:Glycoproteins; D026541:Heymann Nephritis Antigenic Complex; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D010718:Phosphatidylserines; D010743:Phospholipids; D011971:Receptors, Immunologic; D053482:beta 2-Glycoprotein I; D002118:Calcium