Apolipoprotein E5 (Glu(212)->Lys): Increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts

作者：Feussner G^*; Scharnagl H; Scherbaum C; Acar J; Dobmeyer J; Lohrmann J; Wieland H; Marz W

来源：The Journal of Lipid Research, 1996, 37(8): 1632-1645.

DOI：10.1016/s0022-2275(20)39106-9

• apolipoprotein E
• atherosclerosis
• lipoprotein metabolism
• structure-function relationship

A new apolipoprotein (apo) E variant, apoE5 (Glu(212) --> Lys) was identified in a Turkish family. The variant was due to a point mutation (GAG --> AAG) at the first nucleotide position of the codon encoding amino acid residue 212 of the mature apoE. The 23-year-old index patient was heterozygous for the mutation. Examination of the proband's kindred revealed six heterozygous and two homozygous mutation carriers. Compared to non-carriers, carriers of the mutation had slightly higher triglycerides (1.25 versus 1.11 g/l) and lower HDL cholesterol (0.36 versus 0.41 g/l). Very low density lipoproteins (VLDL) from an apoE5 (Glu(212) --> Lys) homozygote displayed enhanced binding (+17%, P < 0.05), but decreased uptake (-35%, P < 0.0001) and degradation (-51%, P < 0.0001) in cultured fibroblasts, compared to E3/3-VLDL. The region of the apoE molecule surrounding residue 212 contains a heparin binding domain. Consistently, the enhanced cell surface binding of E5/5-VLDL was observed in ''wild-type'' Chinese hamster ovary cells (+19%, P < 0.05), but not in proteoglycan-deficient cells. The binding of E5/5-VLDL to heparin was increased (+22%, P < 0.05). As the endocytosis of apoE-containing particles involves the transfer of proteoglycan-bound ligands to lipoprotein receptors, the stronger binding of apoE5 (Glu(212) --> Lys) to proteoglycans could reduce the rate at which the mutant is finally delivered to endocytotic pathways. These data may provide evidence for a functionally important heparin binding site around amino acid residue 212 of the apoE molecule in vivo.

• 出版日期1996-8