Apolipoprotein E5 (Glu212-->Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts.
A new apolipoprotein (apo) E variant, apoE5 (Glu212-->Lys) was identified in a Turkish family. The variant was due to a point mutation (CAG-->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 (Glu212-->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 (Glu212-->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.
Feussner
G
G
Medizinische Universitätsklinik Heidelberg, Germany.
Scharnagl
H
H
Scherbaum
C
C
Acar
J
J
Dobmeyer
J
J
Lohrmann
J
J
Wieland
H
H
März
W
W
D000293:Adolescent; D000328:Adult; D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001667:Binding, Competitive; D016466:CHO Cells / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D004705:Endocytosis / Q000502:physiology; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics / Q000378:metabolism*; D007398:Interpersonal Relations; D008079:Lipoproteins, VLDL / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011509:Proteoglycans / Q000378:metabolism*
D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D011509:Proteoglycans; C049578:apolipoprotein E5; D006493:Heparin