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=Background= | =Background= | ||
Apolipoprotein E is a member of the apolipoprotein family (NMR structure [[217b]]). This soluble protein is produced primarily in the liver and brain; and it is located principally in the plasma and in the central nervous system (CNS)'<ref>Han X. 2010. | Apolipoprotein E is a member of the apolipoprotein family (NMR structure [[217b]]). It was discovered in the early 1970’s as a component of triglyceride-rich lipoprotein complexes. This soluble protein is produced primarily in the liver and brain; and it is located principally in the plasma and in the central nervous system (CNS)'<ref>Han X. 2010. The pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'. The systemic transport of cholesterol and other lipids is this protein's main role in the body '<ref name="OMIM">OMIM.Omim.org/entry/107741.</ref>'. One minor function it exhibits is that of immune regulation '<ref name="OMIM" /ref>'. ApoE also plays a role in synaptic integrity and plasticity '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. Particular isoforms, ε2 and ε4 are implicated in hyperlipoproteinemia (HLP III) and late onset Alzheimer's disease (LOAD). | ||
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=Genetics= | =Genetics= | ||
The ApoE gene stores the information responsible for the protein apolipoprotein E. ApoE's cytogenic location is on the long q arm of chromosome 19, in the 13.2 position (19q13.2). It stretches from base pair 45,409,038 to bp 45,412,649 '<ref>Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.</ref>'. Polymorphisms for this gene include three main alleles, epsilon 2, epsilon 3, and epsilon 4 '<ref>OMIM.Omim.org/entry/107741.</ref>'. The ε3 allele is the most frequent in all human groups. ε4 has a higher frequency in populations such as Pygmies and Khoisan, Aboriginies of Malaysia and Australia, Papuas, some Native Americans, and Lapps. The frequency of ε2 fluctuates without an apparent trend; but, it is | The ApoE gene stores the information responsible for the protein apolipoprotein E. ApoE's cytogenic location is on the long q arm of chromosome 19, in the 13.2 position (19q13.2). It stretches from base pair 45,409,038 to bp 45,412,649 '<ref>Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.</ref>'. Polymorphisms for this gene include three main alleles, epsilon 2, epsilon 3, and epsilon 4 '<ref>OMIM.Omim.org/entry/107741.</ref>'. The ε3 allele is the most frequent in all human groups. ε4 has a higher frequency in populations such as Pygmies and Khoisan, Aboriginies of Malaysia and Australia, Papuas, some Native Americans, and Lapps. The frequency of ε2 fluctuates without an apparent trend; but, it is abcent in Native American populations '<ref>OMIM.Omim.org/entry/107741.</ref>'. | ||
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Three main isoforms exist for human apoE (apoE2, apoE3, apoE4). They are coded for by three different alleles at the same locus (ε2, ε3, ε4). These isoforms of apoE were identified through isoelectric focusing and have 0, +1, and +2 charges to account for the electophoretic differences that they display '<ref>OMIM.Omim.org/entry/107741.</ref>'. ApoE is the most frequent form and is thus considered to be the "wildtype" or parent-type isoform of apoE '<ref>OMIM.Omim.org/entry/107741.</ref>'. | Three main isoforms exist for human apoE (apoE2, apoE3, apoE4). They are coded for by three different alleles at the same locus (ε2, ε3, ε4). These isoforms of apoE were identified through isoelectric focusing and have 0, +1, and +2 charges to account for the electophoretic differences that they display '<ref>OMIM.Omim.org/entry/107741.</ref>'. ApoE is the most frequent form and is thus considered to be the "wildtype" or parent-type isoform of apoE '<ref>OMIM.Omim.org/entry/107741.</ref>'. | ||
The heterogeneity of the three major isoforms can be attributed to small differences within the primary structure, namely cysteine - arginine interchanges, a single residue substitution '<ref>Weisgraber et al. 1981. Human apolipoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of apo-E isoforms The Journal of Biological Chemistry 256(17):9077-9083.</ref>' '<ref>Chou, Chi-Yuan. et al. 2005. Structural Variation in Human Apolipoprotein E3 and E4: Secondary Structure, Tertiary Structure, and Size Distribution. Biophysical Journal 88:455–466.</ref>'. Cysteine-arginine changes are present within the N-terminal domain '<ref>Freiden, Carl and K. Garai. 2012. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. PNAS 109(23):8913-8919.</ref>'. Residues 112 and 158 are the positions accounting for the different isoforms. ApoE2 has a cysteine located positioned at both the 112 and 158 residues (Cys/Cys). Cysteine is present at residue 112 in apoE3 and arginine is present at residue 158 (Cys/Arg). For apoE4, both 112 and 158 are filled by the amino acid arginine (Arg/Arg) '<ref>Weisgraber et al. 1981. Human apolipoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of apo-E isoforms The Journal of Biological Chemistry 256(17):9077-9083.</ref>' '<ref>Chou, Chi-Yuan. et al. 2005. Structural Variation in Human Apolipoprotein E3 and E4: Secondary Structure, Tertiary Structure, and Size Distribution. Biophysical Journal 88:455–466.</ref>'. | The heterogeneity of the three major isoforms can be attributed to small differences within the primary structure, namely cysteine - arginine interchanges, a single residue substitution '<ref>Weisgraber et al. 1981. Human apolipoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of apo-E isoforms The Journal of Biological Chemistry 256(17):9077-9083.</ref>' '<ref>Chou, Chi-Yuan. et al. 2005. Structural Variation in Human Apolipoprotein E3 and E4: Secondary Structure, Tertiary Structure, and Size Distribution. Biophysical Journal 88:455–466.</ref>'. Cysteine-arginine changes are present within the N-terminal domain '<ref>Freiden, Carl and K. Garai. 2012. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. PNAS 109(23):8913-8919.</ref>'. Residues 112 and 158 are the positions accounting for the different isoforms. ApoE2 has a cysteine located positioned at both the 112 and 158 residues (Cys/Cys). Cysteine is present at <scene name='Sandbox_Reserved_595/Residue_112/2'>residue 112</scene> in apoE3 and arginine is present at <scene name='Sandbox_Reserved_595/Residue_158/1'>residue 158</scene> (Cys/Arg). For apoE4, both 112 and 158 are filled by the amino acid arginine (Arg/Arg) '<ref>Weisgraber et al. 1981. Human apolipoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of apo-E isoforms The Journal of Biological Chemistry 256(17):9077-9083.</ref>' '<ref>Chou, Chi-Yuan. et al. 2005. Structural Variation in Human Apolipoprotein E3 and E4: Secondary Structure, Tertiary Structure, and Size Distribution. Biophysical Journal 88:455–466.</ref>'. | ||
[[Image:Apoetable.png|thumb|right|350px]] | [[Image:Apoetable.png|thumb|right|350px]] | ||
Risk associations with diseases and disorders arise from the substitution that occurs at the 112 residue '<ref>Gau et al. 2011. Mass spectrometry-based protein foot printing characterizes the structures of oligomeric apolipoprotein E2, E3, and E4. Biochemistry 50(38):8117-26.</ref>'. As a result of its primary structure, E4 is the most basic isoform '<ref>Weisgraber et al. 1981. Human apolipoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of apo-E isoforms The Journal of Biological Chemistry 256(17):9077-9083.</ref>'. A single | Risk associations with diseases and disorders arise from the substitution that occurs at the 112 residue '<ref>Gau et al. 2011. Mass spectrometry-based protein foot printing characterizes the structures of oligomeric apolipoprotein E2, E3, and E4. Biochemistry 50(38):8117-26.</ref>'. As a result of its primary structure, E4 is the most basic isoform '<ref>Weisgraber et al. 1981. Human apolipoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of apo-E isoforms The Journal of Biological Chemistry 256(17):9077-9083.</ref>'. A single base change, due to a point mutation, at one or two sites in the ε3 gene could account for the E2 and E4 isoforms of apoE; this is a possible explanation given the fact that of the six codons specifying arginine, two of them differ from the cysteine codon merely by one base '<ref>Weisgraber et al. 1981. Human apolipoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of apo-E isoforms The Journal of Biological Chemistry 256(17):9077-9083.</ref>'. Structural differences that exist between the isoforms at higher levels of organization are distant frrom the site of cys-arg substitution '<ref>Freiden, Carl and K. Garai. 2012. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. PNAS 109(23):8913-8919.</ref>'. With regards to other modifications within apoE, E2 and E4 show more similarity to each other than they do to E3; however, E2 is more similar in conformation E3 than E4 is to E3 '<ref>Gau et al. 2011. Mass spectrometry-based protein foot printing characterizes the structures of oligomeric apolipoprotein E2, E3, and E4. Biochemistry 50(38):8117-26.</ref>'. | ||
Different isoforms associate with different lipid particles in the plasma '<ref>Jones, Philip B. et al. 2011. Apoliprotein E: Isoform specific differences in tertiary structure and interaction with amyloid-beta in human alzheimer brain. PLOS One 6(1):e14586.</ref>'. While apoE4 preferentially binds to VLDL, apoE3 and apoE2 have a higher affinity for HDL '<ref>Chou, Chi-Yuan. et al. 2005. Structural Variation in Human Apolipoprotein E3 and E4: Secondary Structure, Tertiary Structure, and Size Distribution. Biophysical Journal 88:455–466.</ref>' '<ref>Dong L-M and K. H. Weisgraber. 1996. Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density | Different isoforms associate with different lipid particles in the plasma '<ref>Jones, Philip B. et al. 2011. Apoliprotein E: Isoform specific differences in tertiary structure and interaction with amyloid-beta in human alzheimer brain. PLOS One 6(1):e14586.</ref>'. While apoE4 preferentially binds to VLDL, apoE3 and apoE2 have a higher affinity for HDL '<ref>Chou, Chi-Yuan. et al. 2005. Structural Variation in Human Apolipoprotein E3 and E4: Secondary Structure, Tertiary Structure, and Size Distribution. Biophysical Journal 88:455–466.</ref>' '<ref>Dong L-M and K. H. Weisgraber. 1996. Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density | ||
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==Type III Hyperlipoproteinemia== | ==Type III Hyperlipoproteinemia== | ||
Familial Type III hyperlipoproteinemia is a genetic lipid disorder that is marked by an increase in the concentrations of plasma cholesterol and | Familial Type III hyperlipoproteinemia is a genetic lipid disorder that is marked by an increase in the concentrations of plasma cholesterol and triglycerides '<ref>Rall, Stanley C. et al. 1981. Human apolipoprotein e the complete amino acid sequence. The Journal of Biological Chemistry 257(8):4171-4178.</ref>'. Normally, in individuals whose apoE is functional, chylomicron remnants and VLDL remnants are rapidly removed from circulation via receptor-mediated endocytosis within the liver. However, this condition develops as a result of apoE that has impaired clearance abilities. When a defect in apoE of this nature is present, delayed clearance in the plasma of triglyceride-rich lipoprotein remants results; significantly elevated levels of cholesterol-encriched remnant lipoproteins are a defining feature of this disorder '<ref>OMIM.Omim.org/entry/107741.</ref>' '<ref>Kashyap, VS et al. 1995. Apolipoprotein E Deficiency in Mice: Gene Replacement and | ||
Prevention of Atherosclerosis Using Adenovirus Vectors. The Journal of Clinical Investigation 96:1612-1620.</ref>'. Individuals homozygous for the ε2 allele are most susceptible. The E2 isoform of apoE exhibits weak or defective binding of remnants to hepatic lipoprotein receptors; the E2 isoform also clears these remnants from the plasma in a sluggish fashion '<ref>OMIM.Omim.org/entry/107741.</ref>'. | Prevention of Atherosclerosis Using Adenovirus Vectors. The Journal of Clinical Investigation 96:1612-1620.</ref>'. Individuals homozygous for the ε2 allele are most susceptible. The E2 isoform of apoE exhibits weak or defective binding of remnants to hepatic lipoprotein receptors; the E2 isoform also clears these remnants from the plasma in a sluggish fashion '<ref>OMIM.Omim.org/entry/107741.</ref>'. | ||
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==References== | ==References== | ||
'<references/>' | '<references/>' | ||