Sandbox Reserved 595: Difference between revisions

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=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 (W).

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 (W). ApoE is the most frequent form and is thus considered to be the "wildtype" isoform of apoE.

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). 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).

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).

Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 (L).

~~==ApoE3==~~

~~ApoE is~~ the ~~most frequent form and is thus considered to be the "wildtype" isoform of apoE~~.

Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 (L). Accessibility of the hydrophobic residues was higher in apoE4 than apoE3 (F). ApoE4 also has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate (F). Domain interaction within apoE is stronger, causing the domains to be closer in proximity to each other, in apoE4 than in apoE; this is true under lipid-bound and lipid-free conditions (E).

~~==ApoE4==~~

ApoE4 has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate (F).

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=Clinical Relevance=

==Late Onset Alzheimer's Disease==

~~Inheritance of the ε4 allele is considered to be the strongest genetic risk factor for late onset Alzheimer's disease (LOAD) (A).~~ Late onset Alzheimer's disease is characterized by the presence of plaques. Amyloid-β, a hydrophobic peptide, is a major component of these plaques (T). ApoE has been observed to tightly bind with Aβ, an interaction that is hypothesized to influence the deposition of Aβ, thus contributing to the pathogenesis of LOAD (F). A significant amount of Aβ is concentrated within the small paopulation of apoE-containing synapses; these two molecules have been observed to be highly colocalized in these synapses (R). Concentrations of amyloid-β in the extracellular space of the brain are indicative of the balance between the synthesis and clearance of Aβ (S). In fact, the Aβ concentration per synaptic terminal is notably lower in control subjects as compared to those exhibiting AD (R). A deficit in clearance, rather than aberrant synthesis, is thought to be a factor in plaque formation (R).

Late onset Alzheimer's disease is characterized by the presence of plaques. Amyloid-β, a hydrophobic peptide, is a major component of these plaques (T). ApoE has been observed to tightly bind with Aβ, an interaction that is hypothesized to influence the deposition of Aβ, thus contributing to the pathogenesis of LOAD (F). A significant amount of Aβ is concentrated within the small paopulation of apoE-containing synapses; these two molecules have been observed to be highly colocalized in these synapses (R). Concentrations of amyloid-β in the extracellular space of the brain are indicative of the balance between the synthesis and clearance of Aβ (S). In fact, the Aβ concentration per synaptic terminal is notably lower in control subjects as compared to those exhibiting AD (R). A deficit in clearance, rather than aberrant synthesis, is thought to be a factor in plaque formation (R). ApoE4's ability to bind to Aβ is impaired, subsequently resulting in a reduced amount of receptor-mediated uptake and cellular metabolism of the apoE/Aβ complex. Therefore, the E4 isoform of apoE is responsible for the reduced Aβ clearance that is characteristic of brains affected by AD (F).

Inheritance of the ε4 allele is considered to be the strongest genetic risk factor for late onset Alzheimer's disease (LOAD) (A,M,N, O). Homozygosity for ε4 is associated with senile plaques that are more developed (O). Isoform-dependent differences in Aβ plaque deposition exist, with apoE4 having the highest association and E2 displaying a seemingly protective role against LOAD (N,S). ApoE4 and its C-terminal truncated fragments have been located in plaques and neurofibrillary tangles within the brain in patients with LOAD (O). Upon interaction with Aβ, apoE4 becomes a partially unfolded intermediary; this transformation occurs due to the frustration of the network of salt bridges. The 4-helix bundle opens, the hydrophobic core becomes exposed, and the protein is rendered incapable of clearing Aβ (T).

==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 (W; 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 (W).

=References=

Sandbox Reserved 595: Difference between revisions

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@@ Line 28: / Line 28: @@
 =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 (W).
+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 (W).  ApoE is the most frequent form and is thus considered to be the "wildtype" isoform of apoE.
-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).  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).
+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).
-Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 (L).
-==ApoE3==
-ApoE is the most frequent form and is thus considered to be the "wildtype" isoform of apoE.
+Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 (L).  Accessibility of the hydrophobic residues was higher in apoE4 than apoE3 (F). ApoE4 also has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate (F). Domain interaction within apoE is stronger, causing the domains to be closer in proximity to each other, in apoE4 than in apoE; this is true under lipid-bound and lipid-free conditions (E).
-==ApoE4==
-ApoE4 has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate (F).
@@ Line 55: / Line 53: @@
 =Clinical Relevance=
 ==Late Onset Alzheimer's Disease==
-Inheritance of the ε4 allele is considered to be the strongest genetic risk factor for late onset Alzheimer's disease (LOAD) (A).  Late onset Alzheimer's disease is characterized by the presence of plaques.  Amyloid-β, a hydrophobic peptide, is a major component of these plaques (T).  ApoE has been observed to tightly bind with Aβ, an interaction that is hypothesized to influence the deposition of Aβ, thus contributing to the pathogenesis of LOAD (F).  A significant amount of Aβ is concentrated within the small paopulation of apoE-containing synapses; these two molecules have been observed to be highly colocalized in these synapses (R).   Concentrations of amyloid-β in the extracellular space of the brain are indicative of the balance between the synthesis and clearance of Aβ (S).  In fact, the Aβ concentration per synaptic terminal is notably lower in control subjects as compared to those exhibiting AD (R).  A deficit in clearance, rather than aberrant synthesis, is thought to be a factor in plaque formation (R).
+  Late onset Alzheimer's disease is characterized by the presence of plaques.  Amyloid-β, a hydrophobic peptide, is a major component of these plaques (T).  ApoE has been observed to tightly bind with Aβ, an interaction that is hypothesized to influence the deposition of Aβ, thus contributing to the pathogenesis of LOAD (F).  A significant amount of Aβ is concentrated within the small paopulation of apoE-containing synapses; these two molecules have been observed to be highly colocalized in these synapses (R).   Concentrations of amyloid-β in the extracellular space of the brain are indicative of the balance between the synthesis and clearance of Aβ (S).  In fact, the Aβ concentration per synaptic terminal is notably lower in control subjects as compared to those exhibiting AD (R).  A deficit in clearance, rather than aberrant synthesis, is thought to be a factor in plaque formation (R).  ApoE4's ability to bind to Aβ is impaired, subsequently resulting in a reduced amount of receptor-mediated uptake and cellular metabolism of the apoE/Aβ complex.  Therefore, the E4 isoform of apoE is responsible for the reduced Aβ clearance that is characteristic of brains affected by AD (F).
+Inheritance of the ε4 allele is considered to be the strongest genetic risk factor for late onset Alzheimer's disease (LOAD) (A,M,N, O).  Homozygosity for ε4 is associated with senile plaques that are more developed (O).  Isoform-dependent differences in Aβ plaque deposition exist, with apoE4 having the highest association and E2 displaying a seemingly protective role against LOAD (N,S). ApoE4 and its C-terminal truncated fragments have been located in plaques and neurofibrillary tangles within the brain in patients with LOAD (O).  Upon interaction with Aβ, apoE4 becomes a partially unfolded intermediary; this transformation occurs due to the frustration of the network of salt bridges.  The 4-helix bundle opens, the hydrophobic core becomes exposed, and the protein is rendered incapable of clearing Aβ (T).
 ==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 (W; 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 (W).
 =References=