DEFINITION
Apolipoproteins are proteins that bind to lipids (oil-soluble substances such as fat and cholesterol) to form lipoproteins, which transport the lipids through the lymphatic and circulatory systems.
The lipid components of lipoproteins are not soluble in water; however, because of their detergent-like (amphipathic) properties, apolipoproteins and other amphipathic molecules (such as phospholipids) can surround the lipids, creating the lipoprotein particle that is itself water-soluble, and can thus be carried through water-based circulation (i.e., blood, lymph).
Apolipoproteins also serve as enzyme cofactors , receptor ligands, and lipid transfer carriers that regulate the metabolism of lipoproteins and their uptake in tissues. ( http://en.wikipedia.org/wiki/Apolipoprotein)
Apolipoprotein E (APOE) is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.
en.wikipedia
THE GENE
CHEMICAL STRUCTURE AND IMAGES
Primary structure:
P02649 APOE_HUMAN
Secondary structure
P02649
Tertiary structure
Protein Aminoacids Percentage (Width 700 px)
SYNTHESIS AND TURNOVER
mRNA synthesis
ApoE mRNA first appears as monocytes differentiate into macrophages, and this expression is paralleled by the secretion of ApoE by the cells. In mature macrophages ApoE synthesis and secretion are decreased by activation of macrophages with endotoxin and interferon-gamma. Although these macrophages contain abundant translatable ApoE mRNA, little ApoE is synthesized, suggesting that this decrease occurs largely at the translational level. ApoE is also controlled at the level of secretion. ApoE is concentrated in the Golgi complex of macrophages and is also found in endoplasmic reticulum, secretion vesicles and coated vesicles. When macrophages come in contact with immune complexes the intracellular ApoE compartment degranulates rapidly. Therefore, ApoE is regulated at the levels of secretion, translation and transcription.
The cell and molecular biology of apolipoprotein E synthesis by macrophages - 1986
Protein synthesis
Apolipoprotein E has two functional domains. These two functional domains of apoE are separated by thrombin cleavage, which produces two fragments: a 22 kDa fragment at the amino-terminus of the protein, which contains the receptor-binding domain of the protein; and a 10 kDa fragment at the carboxyl-terminus of the protein, which contains the lipid-binding domain.
The crystal structure of the 22 kDa amino-terminal domain reveals four a -helical domains, and provides
crucial insights into the mechanisms by which amino acid interactions within the 22 kDa amino-terminal
domain functionally alter the ability of the 10 kDa carboxyl-terminal domain to bind various phospholipid
particles. ApoE2 and apoE3 preferentially bind small HDL particles, whereas apoE4 preferentially binds the
larger VLDL particles. Because the amino acids that differentiate the three isoforms are located in the 22 kDa amino-terminal domain (at positions 112 and 158) and the lipid-binding domain is located in the 10 kDa
carboxyl-terminal domain, molecular interactions between these domains are functionally important.
Some authors studied the domain±domain interactions of apoE by which the amino acids that determine the particular isoform (in the amino-terminal domain influence binding of phospholipids by the carboxylterminal
domain. ApoE4 (with an Arg112) causes Arg61 in the amino-terminal domain to interact with Glu255 in
the carboxyl-terminal domain, and thereby causes preferential binding of VLDL. In contrast, apoE2 and
apoE3 (both with Cys112) do not display this domain interaction, resulting in preferential binding of HDL.
The cell and molecular biology of apolipoprotein E synthesis by macrophages - 1986
post-translational modifications
Some studies indicate that alteration of sterol content does not regulate macrophage apoE production at a translational or post-translational locus but that incubation with HDL3 or phospholipid vesicles can enhance apoprotein E production independent of changes in apoE gene transcription or apoE synthesis.
Post-translational regulation of macrophage apoprotein E production - Jan 1992
degradation
The results of some studies indicate that newly synthesized apoE in the macrophage can be degraded in an intermediate density nonlysosomal cellular compartment, which is sensitive to proteasomal inhibitors.
Alteration of cellular lipid homeostasis by preincubation in sterol/oxysterol or acetylated low density lipoprotein inhibits apoE, but not total protein, degradation in this fraction.
Inhibition of the degradation of apoE in this fraction likely contributes to the increased apoE secretion observed in sterol-enriched cells.
Degradation of macrophage ApoE in a nonlysosomal compartment. Regulation by sterols - dec 1997
CELLULAR FUNCTIONS
The generation and function of soluble apoE receptors in the CNS - 2006
REGULATION
Apolipoprotein E has critical roles in the protection against atherosclerosis and is understood to follow the classical constitutive secretion pathway. Recent studies have indicated that the secretion of apoE from macrophages is a regulated process of unexpected complexity. Cholesterol acceptors such as apolipoprotein A-I, high density lipoprotein, and phospholipid vesicles can stimulate apoE secretion. The ATP binding cassette transporter ABCA1 is involved in basal apoE secretion and in lipidating apoE-containing particles secreted by macrophages. However, the stimulation of apoE secretion by apoA-I is ABCA1-independent, indicating the existence of both ABCA1-dependent and -independent pathways of apoE secretion. The release of apoE under basal conditions is also regulated, requiring intact protein kinase A activity, intracellular calcium, and an intact microtubular network. Mathematical modeling of apoE turnover indicates that whereas some pools of apoE are committed to either secretion or degradation, other pools can be diverted from degradation toward secretion.
Regulation of Endogenous Apolipoprotein E Secretion by Macrophages - 2008
DIAGNOSTIC USE
The e4 version of the APOE gene increases an individual's risk for developing late-onset Alzheimer disease. People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk. The APOE e4 allele may also be associated with an earlier onset of memory loss and other symptoms. It is not known how the APOE e4 allele is related to the risk of Alzheimer disease. However, researchers have found that this allele is associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of affected people. A buildup of toxic amyloid beta peptide and amyloid plaques may lead to the death of neurons and the progressive signs and symptoms of this disorder. It is important to note that people with the APOE e4 allele inherit an increased risk of developing Alzheimer disease, not the disease itself. Not all people with Alzheimer disease have the APOE e4 allele, and not all people who have this allele will develop the disease. Variants of apolipoprotein E have been studied extensively as risk factors for many different conditions. For example, APOE alleles have been shown to influence the risk of cardiovascular diseases. People who carry at least one copy of the APOE e4 allele have an increased chance of developing atherosclerosis, which is an accumulation of fatty deposits and scar-like tissue in the lining of the arteries. This progressive narrowing of the arteries increases the risk of heart attack and stroke. The APOE e2 allele has been shown to greatly increase the risk of a rare condition called hyperlipoproteinemia type III. Most people with this disorder have two copies of the APOE e2 allele, leading researchers to conclude that the e2 allele plays a critical role in the development of the condition. Hyperlipoproteinemia type III is characterized by increased blood levels of cholesterol, certain fats called triglycerides, and molecules called beta-very low-density lipoproteins (beta-VLDLs), which carry cholesterol and lipoproteins in the bloodstream. A buildup of cholesterol and other fatty materials can lead to the formation of small, yellow skin growths called xanthomas and the development of atherosclerosis. APOE gene variants have also been studied as a potential risk factor for age-related macular degeneration, an eye disease that is a leading cause of vision loss among older people worldwide. Some studies have suggested that having at least one copy of the APOE e4 allele may help protect against this disease or delay the onset of vision loss, while having at least one copy of the APOE e2 allele may increase the risk of this disease or cause symptoms to appear earlier. However, other studies have not found these associations. More research is needed to clarify what role, if any, APOE gene variants play in the development of age-related macular degeneration.
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by Antonio Manca et Francesca Saba
