Binding studies showed that lipid-bound apoE3 has 55% reduced LDL receptor binding capacity compared to apoE3 and the 22-kDa domain of lipid-bound apoE3 has 48% reduced HSPG binding capacity compared to apoE3-22kDa. Homozygosity and heterozygocity for the apoE variant apoE3 has also been associated with severe type III HLP.
Additionally, it has been shown that homozygosity for apoE3 and heterozygocity for apoE3 with all apoE alleles result also in type III HLP, but the penetrance of the disease is incomplete. In vitro studies showed that lipid-bound apoE3 displays a reduction of 60% in LDL receptor binding capacity as compared to wild-type apoE3. Specifically, heterozygosity for the apoE variant apoE3 (previously designated apoE2 Christchurch) with the apoE2 allele results in type III HLP. Most of these apoE mutations are between residues 136 to 150. Besides apoE2, which is associated with a recessive form of type III HLP, a variety of rare naturally-occurring apoE mutations have also been described that are associated with a dominant mode of inheritance of type III HLP which is expressed at an early age. This lipid disorder is characterized by xanthomas, elevated plasma cholesterol and triglyceride levels, and is associated with premature atherosclerosis in humans and experimental animal models of the disease. Homozygosity for the apoE2 isoform, which has defective in vitro binding capacity to the LDL receptor, is present in the vast majority of subjects with type III hyperlipoproteinemia (HLP). In apoE3 and apoE2 Arg-61 and Glu-255 do not interact. This orientation allows Arg-61 to form a salt bridge with Glu-255 in the C-terminal domain. In apoE4, the N- and C-terminal domains interact differently than in the other isoforms, since Arg-112 results in the orientation of the Arg-61 side chain in the N-terminal domain of apoE4 away from the four-helix bundle. The C-terminal domain is highly α-helical, as determined by computer modeling and circular dichroism spectroscopy, ,, but its exact structure is unknown. X-ray crystallography studies showed that the N-terminal domain is folded into a four-helix bundle of amphipathic α-helices spanning residues 24-164 that are stabilized by hydrophobic interactions and salt bridges. Digestion with thrombin produces a 22-kDa N-terminal fragment (residues 1 to 191) and a 10-kDa C-terminal fragment (residues 216 to 299). In the lipid-free state apoE is folded into two independent structural domains. ApoE4 is a major genetic risk factor for late-onset Alzheimer's disease. ApoE3, the most common form, contains cysteine at position 112 and arginine at position 158, whereas apoE2 has two cysteine residues and apoE4 has two arginine residues at these two positions.
ApoE contains 299 residues and has three common isoforms (apoE2, apoE3, apoE4) in the general population, each differing in the amino acid positions 112 and 158. ApoE is also involved in cholesterol efflux processes, and thus may contribute to cell and tissue cholesterol homeostasis. Additionally, apoE interacts with other members of the LDL receptor family and cell-surface heparan sulfate proteoglycans (HSPGs). ApoE mediates the hepatic clearance of lipoprotein remnants from circulation serving as a ligand for the low-density lipoprotein (LDL) receptor.
Apolipoprotein E (apoE) is a major protein of the lipoprotein transport system that plays critical role in the protection from atherosclerosis and dyslipidemia.
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