Sandbox Reserved 595: Difference between revisions
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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. T he 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 | 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. T he 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>OMIM.Omim.org/entry/107741.</ref>'. One minor function it may exhibit is that of immune regulation '<ref>OMIM.Omim.org/entry/107741.</ref>'. ApoE may also play a role in synaptic integrity and plasticity (R). Particular isoforms, ε2 and ε4 are implicated in hyperlipoproteinemia (HLP III) and late onset Alzheimer's disease (LOAD). | ||
=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 (X). Polymorphisms for this gene include three main alleles, epsilon 2, epsilon 3, and epsilon 4 | 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 (X). 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 abscent in Native American populations '<ref>OMIM.Omim.org/entry/107741.</ref>'. | ||
=Structure= | =Structure= | ||
<Structure load='1NFN' size='500' frame='true' align='right' caption='3-D Rendering of ApoE3 N-terminus' scene='Insert optional scene name here' /> | <Structure load='1NFN' size='500' frame='true' align='right' caption='3-D Rendering of ApoE3 N-terminus' scene='Insert optional scene name here' /> | ||
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ApoE exhibits extensive domain interactions. Hydrogen bonds and salt-bridges act to shield the major LDLR-binding region. This protein's unique topology regulates its tertiary structure in order to solely permit one conformation upon binding in a two-step manner. Lipid-free and partially lipidated ApoE are thwarted from prematurely binding to ApoE receptors by the tertiary structure. Therefore, the optimal receptor-binding affinity of fully lipidated ApoE is guaranteed. An active conformation for biding to members of the low-density lipoprotein receptor family is achieved through binding to lipids and HSPGs (V). | ApoE exhibits extensive domain interactions. Hydrogen bonds and salt-bridges act to shield the major LDLR-binding region. This protein's unique topology regulates its tertiary structure in order to solely permit one conformation upon binding in a two-step manner. Lipid-free and partially lipidated ApoE are thwarted from prematurely binding to ApoE receptors by the tertiary structure. Therefore, the optimal receptor-binding affinity of fully lipidated ApoE is guaranteed. An active conformation for biding to members of the low-density lipoprotein receptor family is achieved through binding to lipids and HSPGs (V). | ||
As was aforementioned, ApoE interacts with multiple partners, including LDLRs, cell-surface HSPGs, ATP-binding cassette protein 1 (ABCA1), and low-density lipoprotein-related proteins (LRPs). It binds with lipids and cholesterol, with high-affinity, to form lipoprotein particles | As was aforementioned, ApoE interacts with multiple partners, including LDLRs, cell-surface HSPGs, ATP-binding cassette protein 1 (ABCA1), and low-density lipoprotein-related proteins (LRPs). It binds with lipids and cholesterol, with high-affinity, to form lipoprotein particles '<ref>OMIM.Omim.org/entry/107741.</ref>'. ''In vivo'', ApoE is almost always associated with lipids and cholesterol. Concentrations of lipid-free ApoE are expected to be insignificant (M). | ||
==Quarternary Structural Features== | ==Quarternary Structural Features== | ||
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=Isoforms= | =Isoforms= | ||
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 | 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>'(G). | ||
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 (F,G). Cysteine-arginine changes are present within the N-terminal domain (M). 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) (F,G). Risk associations with diseases and disorders arise from the substitution that occurs at the 112 residue (N). As a result of its primary structure, E4 is the most basic isoform (G). A single pase 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 (G). Structural differences that exist between the isoforms at higher levels of organization are distant frrom the site of cys-arg substitution (M). 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 (N). | 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 (F,G). Cysteine-arginine changes are present within the N-terminal domain (M). 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) (F,G). Risk associations with diseases and disorders arise from the substitution that occurs at the 112 residue (N). As a result of its primary structure, E4 is the most basic isoform (G). A single pase 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 (G). Structural differences that exist between the isoforms at higher levels of organization are distant frrom the site of cys-arg substitution (M). 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 (N). | ||
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==Immunological== | ==Immunological== | ||
ApoE can bind lipid antigens. Once binding occurs, apoE delivers the antigens, via receptor-mediated uptake, into endosomal compartments containing CD1 in antigen-processing cells. This protein can be secreted by antigen-presenting cells for the purpose of surveying the local environment and transfer microbial lipids from infected cells to bystander antigen-presenting cells. In one study, apoE mediated the presentation of serum-bovine lipid antigens. In this way, the immune system has co-opted a component of lipid metabolism in order to raise immunologic responses to lipid antigens | ApoE can bind lipid antigens. Once binding occurs, apoE delivers the antigens, via receptor-mediated uptake, into endosomal compartments containing CD1 in antigen-processing cells. This protein can be secreted by antigen-presenting cells for the purpose of surveying the local environment and transfer microbial lipids from infected cells to bystander antigen-presenting cells. In one study, apoE mediated the presentation of serum-bovine lipid antigens. In this way, the immune system has co-opted a component of lipid metabolism in order to raise immunologic responses to lipid antigens '<ref>OMIM.Omim.org/entry/107741.</ref>'. | ||
=Clinical Relevance= | =Clinical Relevance= | ||
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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 triglyceride levels (Rall 82). Normally, in individuals whose apoE is functional, chylomicron remnants and VLDL remnants are rapidly removed from circulation via recptor-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 ( | Familial Type III hyperlipoproteinemia is a genetic lipid disorder that is marked by an increase in the concentrations of plasma cholesterol and triglyceride levels (Rall 82). Normally, in individuals whose apoE is functional, chylomicron remnants and VLDL remnants are rapidly removed from circulation via recptor-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>' (Kashyap). 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>'. | ||
=References= | =References= | ||
