Sandbox Reserved 595: Difference between revisions

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=Background=

Apolipoprotein E is a member of the apolipoprotein family. 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) (AA). The systemic transport of cholesterol and other lipids is this protein's main role in the body (W). One minor function it may exhibit is that of immune regulation (W). 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).

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) (AA). The systemic transport of cholesterol and other lipids is this protein's main role in the body (W). One minor function it may exhibit is that of immune regulation (W). 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=

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 (W). 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 (W).

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Apolipoprotein E is a polymorphic glycoprotein that consists of 299 amino acids (A,F). It has a molecular weight of 34kDa (G). The primary structure for ApoE is rich in the amino acid <scene name='Sandbox_Reserved_595/Arginine/1'>arginine</scene>

ApoE folds into two independent structural domains that are connected via a hinge region (A,F,M). The amino-terminal domain has a molecular weight of 2kDa and is comprised of the amino acid residues 1-199 (C,F,J,M). It is a globular domain consisting of an antiparallel bundle of 4 amphipathic <scene name='Sandbox_Reserved_595/4-helix_bundle/1'>alpha-helices</scene>, rich in basic amino acids; pronounced kinks are present in the helices near the end of the 4-helix bundle that correspond with the protein's lipid binding ability (C,F,J,L). In the fourth helix, the residues between 134-150, known as the <scene name='Sandbox_Reserved_595/Ldl-r_binding_region/1'>low density lipoprotein receptor binding region</scene>, are responsible for ApoE's ability to bind to members of the LDL receptor family (C,F,J,L). This domain also contains the variable <scene name='Sandbox_Reserved_595/Residues_112_and_158/3'>residues 112 and 158</scene> (112 blue & 158 in red), which are responsible for much of the differences between the three isoforms of apoE.

ApoE folds into two independent structural domains that are connected via a hinge region (A,F,M). The amino-terminal domain has a molecular weight of 2kDa and is comprised of the amino acid residues 1-199 (PDB entry [[1NFN]])(C,F,J,M). It is a globular domain consisting of an antiparallel bundle of 4 amphipathic <scene name='Sandbox_Reserved_595/4-helix_bundle/1'>alpha-helices</scene>, rich in basic amino acids; pronounced kinks are present in the helices near the end of the 4-helix bundle that correspond with the protein's lipid binding ability (C,F,J,L). In the fourth helix, the residues between 134-150, known as the <scene name='Sandbox_Reserved_595/Ldl-r_binding_region/1'>low density lipoprotein receptor binding region</scene>, are responsible for ApoE's ability to bind to members of the LDL receptor family (C,F,J,L). This domain also contains the variable <scene name='Sandbox_Reserved_595/Residues_112_and_158/3'>residues 112 and 158</scene> (112 blue & 158 in red), which are responsible for much of the differences between the three isoforms of apoE.

The carboxyl-terminal domain is 10kD respectively, and consists of the residues 216-299 (C,F). It presents a large exposed hydrophobic surface that is well-suited for interacting with multiple binding partners, including lipids, heparin sulfate proteoglycans (HSPGs), and amyloid beta peptides (Aβ) (V). This domain harbors high-affinity lipid binding properties and is therefore capable of anchoring lipoprotein particles; it also contains sites that mediate ApoE self-association (C,D,I,J,P). The C-terminal domain includes two kinds of amphipathic alpha helices. The first of these alpha helices is a class A helix (residues 216-266) and the second is a class G helix (residues 273-299) (D). Residues 230-270 in the C-terminal domain are crucial for oligomer formation(M). Those residues that are important for the initiation of lipid binding to ApoE are 261-272 (M).

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=Clinical Relevance=

==Late Onset Alzheimer's Disease==

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).

Late onset Alzheimer's disease is characterized by the presence of plaques. [[Amyloid beta]], 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).

Sandbox Reserved 595: Difference between revisions

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@@ Line 5: / Line 5: @@
 =Background=
-Apolipoprotein E is a member of the apolipoprotein family.  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) (AA).  The systemic transport of cholesterol and other lipids is this protein's main role in the body (W).  One minor function it may exhibit is that of immune regulation (W).  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).
+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) (AA).  The systemic transport of cholesterol and other lipids is this protein's main role in the body (W).  One minor function it may exhibit is that of immune regulation (W).  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=
 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 (W).  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 (W).
@@ Line 13: / Line 13: @@
 Apolipoprotein E is a polymorphic glycoprotein that consists of 299 amino acids (A,F).  It has a molecular weight of 34kDa (G).  The primary structure for ApoE is rich in the amino acid <scene name='Sandbox_Reserved_595/Arginine/1'>arginine</scene>
-ApoE folds into two independent structural domains that are connected via a hinge region (A,F,M).  The amino-terminal domain has a molecular weight of 2kDa and is comprised of the amino acid residues 1-199 (C,F,J,M).  It is a globular domain consisting of an antiparallel bundle of 4 amphipathic <scene name='Sandbox_Reserved_595/4-helix_bundle/1'>alpha-helices</scene>, rich in basic amino acids;  pronounced kinks are present in the helices near the end of the 4-helix bundle that correspond with the protein's lipid binding ability (C,F,J,L).  In the fourth helix, the residues between 134-150, known as the <scene name='Sandbox_Reserved_595/Ldl-r_binding_region/1'>low density lipoprotein receptor binding region</scene>, are responsible for ApoE's ability to bind to members of the LDL receptor family (C,F,J,L).  This domain also contains the variable <scene name='Sandbox_Reserved_595/Residues_112_and_158/3'>residues 112 and 158</scene> (112 blue & 158 in red), which are responsible for much of the differences between the three isoforms of apoE.
+ApoE folds into two independent structural domains that are connected via a hinge region (A,F,M).  The amino-terminal domain has a molecular weight of 2kDa and is comprised of the amino acid residues 1-199 (PDB entry [[1NFN]])(C,F,J,M).  It is a globular domain consisting of an antiparallel bundle of 4 amphipathic <scene name='Sandbox_Reserved_595/4-helix_bundle/1'>alpha-helices</scene>, rich in basic amino acids;  pronounced kinks are present in the helices near the end of the 4-helix bundle that correspond with the protein's lipid binding ability (C,F,J,L).  In the fourth helix, the residues between 134-150, known as the <scene name='Sandbox_Reserved_595/Ldl-r_binding_region/1'>low density lipoprotein receptor binding region</scene>, are responsible for ApoE's ability to bind to members of the LDL receptor family (C,F,J,L).  This domain also contains the variable <scene name='Sandbox_Reserved_595/Residues_112_and_158/3'>residues 112 and 158</scene> (112 blue & 158 in red), which are responsible for much of the differences between the three isoforms of apoE.
 The carboxyl-terminal domain is 10kD respectively, and consists of the residues 216-299 (C,F).  It presents a large exposed hydrophobic surface that is well-suited for interacting with multiple binding partners, including lipids, heparin sulfate proteoglycans (HSPGs), and amyloid beta peptides (Aβ) (V).  This domain harbors high-affinity lipid binding properties and is therefore capable of anchoring lipoprotein particles; it also contains sites that mediate ApoE self-association (C,D,I,J,P).  The C-terminal domain includes two kinds of amphipathic alpha helices.  The first of these alpha helices is a class A helix (residues 216-266) and the second is a class G helix (residues 273-299) (D).  Residues 230-270 in the C-terminal domain are crucial for oligomer formation(M).  Those residues that are important for the initiation of lipid binding to ApoE are 261-272 (M).
@@ Line 50: / Line 50: @@
 =Clinical Relevance=
 ==Late Onset Alzheimer's Disease==
-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).
+Late onset Alzheimer's disease is characterized by the presence of plaques.  [[Amyloid beta]], 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).