Apolipoprotein E5 (Glu212–>Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts
| Autor: | J. Acar, Winfried März, C Scherbaum, J Dobmeyer, H. Scharnagl, Heinrich Wieland, J Lohrmann, Giso Feussner |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Apolipoprotein E
Very low-density lipoprotein Mutation Apolipoprotein B biology Cholesterol Point mutation Mutant QD415-436 Cell Biology medicine.disease_cause Biochemistry Molecular biology Cell biology chemistry.chemical_compound Endocrinology chemistry biology.protein medicine lipids (amino acids peptides and proteins) Binding site |
| Zdroj: | Journal of Lipid Research, Vol 37, Iss 8, Pp 1632-1645 (1996) |
| ISSN: | 0022-2275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|