Sandbox Reserved 595

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This Sandbox is Reserved from Feb 1, 2013, through May 10, 2013 for use in the course "Biochemistry" taught by Irma Santoro at the Reinhardt University. This reservation includes Sandbox Reserved 591 through Sandbox Reserved 599.
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BackgroundBackground

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)'[1]'. The systemic transport of cholesterol and other lipids is this protein's main role in the body '[2]'. One minor function it exhibits is that of immune regulation 'Cite error: Invalid parameter in <ref> tag'. Particular isoforms, ε2 and ε4 are implicated in hyperlipoproteinemia (HLP III) and late onset Alzheimer's disease (LOAD).

GeneticsGenetics

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 '[3]'. Polymorphisms for this gene include three main alleles, epsilon 2, epsilon 3, and epsilon 4 '[4]'. 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 '[5]'.

StructureStructure

3-D Rendering of ApoE3 N-terminus

Drag the structure with the mouse to rotate

Primary Structural FeaturesPrimary Structural Features

Apolipoprotein E is a polymorphic glycoprotein that consists of 299 amino acids '[6]' '[7]'. It has a molecular weight of 34kDa '[8]'. The primary structure for ApoE is rich in the amino acid

ApoE folds into two independent structural domains that are connected via a hinge region '[9]' '[10]' '[11]'. The amino-terminal domain has a molecular weight of 2kDa and is comprised of the amino acid residues 1-199 (PDB entry 1nfn)'[12]' '[13]' '[14]' '[15]'. It is a globular domain consisting of an antiparallel bundle of 4 amphipathic , 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 '[16]' '[17]' '[18]' '[19]'. In the fourth helix, the residues between 134-150, known as the , are responsible for ApoE's ability to bind to members of the LDL receptor family '[20]' '[21]' '[22]' '[23]'. This domain also contains the variable (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 '[24]' '[25]'. 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) '[26]'. 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 '[27]' '[28]' '[29]' '[30]'. 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) '[31]'. Residues 230-270 in the C-terminal domain are crucial for oligomer formation '[32]'. Those residues that are important for the initiation of lipid binding to ApoE are 261-272 '[33]'.

Connecting the N-terminal and C-terminal domains is the flexible hinge region, which extends approximately from residue 165 to residue 215 '[34]' '[35]'. This region is protease sensitive '[36]'.

Full Protein (Chou et al. 2005)

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 '[37]'.

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 '[38]'. In vivo, ApoE is almost always associated with lipids and cholesterol. Concentrations of lipid-free ApoE are expected to be insignificant '[39]'.

Quarternary Structural FeaturesQuarternary Structural Features

ApoE proteins self-associate in order to form dimers, tetrameters, and higher aggregates. These phenomena occur in a concentration, pH, and temperature-dependent manner '[40]'. Oligomerization also correlates with the length of the C-terminal domain '[41]'. Resulting from this protein's propensity to aggregate is difficulty in determining the full-length three-dimensional structure '[42]'. At μM concentrations, ApoE primarily exists as a tetrameter. When members of a tetrameter dissociate, the subsequent dimeric and monomeric forms retain their structure; dissociation from a tetrameter may serve to open new ligand binding sites '[43]'.

IsoformsIsoforms

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 '[44]'. ApoE is the most frequent form and is thus considered to be the "wildtype" or parent-type isoform of apoE '[45]'.

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 '[46]' '[47]'. Cysteine-arginine changes are present within the N-terminal domain '[48]'. 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 in apoE3 and arginine is present at (Cys/Arg). For apoE4, both 112 and 158 are filled by the amino acid arginine (Arg/Arg) '[49]' '[50]'.

Risk associations with diseases and disorders arise from the substitution that occurs at the 112 residue '[51]'. As a result of its primary structure, E4 is the most basic isoform '[52]'. 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 '[53]'. Structural differences that exist between the isoforms at higher levels of organization are distant frrom the site of cys-arg substitution '[54]'. 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 '[55]'.

Different isoforms associate with different lipid particles in the plasma '[56]'. While apoE4 preferentially binds to VLDL, apoE3 and apoE2 have a higher affinity for HDL '[57]' '[58]'. Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 '[59]'. Accessibility of the hydrophobic residues was higher in apoE4 than apoE3 '[60]'. ApoE4 also has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate '[61]'. 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 '[62]'. Arginine 61 and glutamic acid 255 form a salt brigde that mediates the electrostatic interaction of C-T and N-T domains in apoE; the presence of arg112 in apoE4 appears to alter the salt-bridge in such as way as to enhance domain interaction '[63]' '[64]' '[65]'. Arg112 in apoE4 forms a salt-bridge with Glu109, a feature that apoE3 lacks '[66]'.

FunctionFunction

Lipid MetabolismLipid Metabolism

The protein, apolipoprotein E, has an important role in lipid metabolism; principally, it serves as a carrier protein. ApoE combines with lipids in the body to form lipoprotein particles '[67]' '[68]'. These lipoprotein particles have hydrophobic lipids situated at the core and hydrophilic side chains made of amino acids '[69]'. Specifically, apoE is responsible for packaging cholesterol,other lipids, and fat soluble vitamins and transporting them systemically '[70][71]'.

Various Functions of ApoE (Zhang et al. 2011)

Synthesis of this protein primarily occurs in the liver; approximately three-fourths of plasma apoE is generated in the liver by hepatic parenchymal cells '[72]'. In this location, apoE is included as a major component of very-low density lipoproteins (VLDL) '[73]' '[74]'. VLDL serves to remove excess cholesterol from the blood and to carry it to the liver for processing. Thus, apoE acts as a cholesterol chaperone '[75]'. Maintaining optimal levels of cholesterol is crucial for the prevention of disorders that affect the heart and blood levels '[76]'. Triglycerides are also transported to the liver tissue with the aid of VLDL '[77]'. ApoE is essential for the normal catabalism of triglyceride-rich lipoprotein constituents '[78]'. In the plasma, apoE will associate with most lipoproteins, however, n the central nervous system, it mainly associates with high-density lipoproteins (HDL) '[79]'.

Another way in which apoE is involved in the metabolsim of lipids is through binding to the low denstiy lipoprotein receptor; apoE assists in both the transportation of lipids and the facilitation of their uptake. ApoE mediates the receptor binding of apoE lipoprotein particles to the LDL recptor, an action that initiates the cellular uptake of lipoproteins '[80]'. Following the receptor-mediated endocytosis of apoE-containing lipoprotein particles by LDL receptor family member, apoE may undero one of two fates. ApoE can either be degraded, or it can be recycled back to the cell surface '[81]'. One other function that apoE plays with regards to lipid metabolism takes place within the intestinal tract. ApoE has the ability to incorporate into intestinally synthesized chylomicrons. By doing so, apoE can transport dietary triglycerides and cholesterol '[82]'.

NeurologicalNeurological

In the brain, apoE is primarily produced by astrocytes. ApoE in the brain is thought to deliver cholesterol and other lipids to neurons through the process of receptor-mediated endocytosis. It may also play in important role in synaptic integrity and plasticity '[83]'. For, cholesterol released from apoE-containing lipoprotein particles is used to support synaptogenesis as well as the maintenance of synaptic connections '[84]'.

ImmunologicalImmunological

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 '[85]'.

Clinical RelevanceClinical Relevance

Late Onset Alzheimer's DiseaseLate Onset Alzheimer's Disease

Late onset Alzheimer's disease is characterized by the presence of plaques. Amyloid beta, a hydrophobic peptide, is a major component of these plaques '[86]'. 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 '[87]'. 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 '[88]'. Concentrations of amyloid-β in the extracellular space of the brain are indicative of the balance between the synthesis and clearance of Aβ '[89]'. In fact, the Aβ concentration per synaptic terminal is notably lower in control subjects as compared to those exhibiting AD '[90]'. A deficit in clearance, rather than aberrant synthesis, is thought to be a factor in plaque formation '[91]'. 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 '[92]'.

Inheritance of the ε4 allele is considered to be the strongest genetic risk factor for late onset Alzheimer's disease (LOAD) '[93]' '[94]'. Homozygosity for ε4 is associated with senile plaques that are more developed '[95]'. Isoform-dependent differences in Aβ plaque deposition exist, with apoE4 having the highest association and E2 displaying a seemingly protective role against LOAD '[96]'. ApoE4 and its C-terminal truncated fragments have been located in plaques and neurofibrillary tangles within the brain in patients with LOAD '[97]'. 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 '[98]'.

Type III HyperlipoproteinemiaType III Hyperlipoproteinemia

Familial Type III hyperlipoproteinemia is a genetic lipid disorder that is marked by an increase in the concentrations of plasma cholesterol and triglycerides '[99]'. 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 '[100]' '[101]'. 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 '[102]'.

ReferencesReferences

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  1. ↑ 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.
  2. ↑ OMIM.Omim.org/entry/107741.
  3. ↑ Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.
  4. ↑ OMIM.Omim.org/entry/107741.
  5. ↑ OMIM.Omim.org/entry/107741.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Narayanaswami, V. et al. 2001. Lipid association-induced N- and C- terminal domain reorganization in human apolipoprotein E3. J Biol. Chem 276(41):37853-60.
  15. ↑ Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.
  16. ↑ 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.
  17. ↑ Narayanaswami, V. et al. 2001. Lipid association-induced N- and C- terminal domain reorganization in human apolipoprotein E3. J Biol. Chem 276(41):37853-60.
  18. ↑ Hsieh, Yi-Hui and Chi-Yuan Chou. 2011. apolipoprotein E 72-166 peptides in both aqueous and lipid environments. Journal of Biomedical Science 18:14.
  19. ↑ Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.
  20. ↑ 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.
  21. ↑ Narayanaswami, V. et al. 2001. Lipid association-induced N- and C- terminal domain reorganization in human apolipoprotein E3. J Biol. Chem 276(41):37853-60.
  22. ↑ Hsieh, Yi-Hui and Chi-Yuan Chou. 2011. apolipoprotein E 72-166 peptides in both aqueous and lipid environments. Journal of Biomedical Science 18:14.
  23. ↑ Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.
  24. ↑ 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.
  25. ↑ Narayanaswami, V. et al. 2001. Lipid association-induced N- and C- terminal domain reorganization in human apolipoprotein E3. J Biol. Chem 276(41):37853-60.
  26. ↑ Chen, J et al. 2011. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci USA 108(36):14813-8.
  27. ↑ Narayanaswami, V. et al. 2001. Lipid association-induced N- and C- terminal domain reorganization in human apolipoprotein E3. J Biol. Chem 276(41):37853-60.
  28. ↑ Tamamizu-Kato S et al. 2008. Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E. Biochemistry 4(18):5225-34.
  29. ↑ Richard, UC et al. 2011. Hydrogen/Deuterium Exchange and Electron-Transfer Dissociation Mass Spectrometry Determine the Interface and Dynamics of Apolipoprotein E Oligomerization. Biochemistry 50(43):9273-82.
  30. ↑ Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.
  31. ↑ Tamamizu-Kato S et al. 2008. Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E. Biochemistry 4(18):5225-34.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ Phu, MG et al. 2005. Fluorescence resonance energy transfer analysis of apolipoprotein E C-terminal domain and amyloid beta peptide (1-42) interaction. J Neuro Sci Res 80(6):877-86.
  35. ↑ 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 lipoproteins. J. Biol. Chem.271:19053–19057.
  36. ↑ 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.
  37. ↑ Chen, J et al. 2011. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci USA 108(36):14813-8.
  38. ↑ OMIM.Omim.org/entry/107741.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ Richard, UC et al. 2011. Hydrogen/Deuterium Exchange and Electron-Transfer Dissociation Mass Spectrometry Determine the Interface and Dynamics of Apolipoprotein E Oligomerization. Biochemistry 50(43):9273-82.
  43. ↑ Garai, K and Frieden C. 2010. The association−dissociation behavior of the ApoE proteins: kinetic and equilibrium studies. Biochemistry 49(44):9533-41.
  44. ↑ OMIM.Omim.org/entry/107741.
  45. ↑ OMIM.Omim.org/entry/107741.
  46. ↑ 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.
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 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.
  51. ↑ 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.
  52. ↑ 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.
  53. ↑ 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.
  54. ↑ 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.
  55. ↑ 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.
  56. ↑ 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.
  57. ↑ 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.
  58. ↑ 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 lipoproteins. J. Biol. Chem.271:19053–19057.
  59. ↑ Hsieh, Yi-Hui and Chi-Yuan Chou. 2011. apolipoprotein E 72-166 peptides in both aqueous and lipid environments. Journal of Biomedical Science 18:14.
  60. ↑ 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.
  61. ↑ 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.
  62. ↑ Hatters, DM et al. 2005. Modulation of apolipoprotein E structure by domain interaction: differences in lipid-bound and lipid-free forms. J Biol Chem 280(4):34288-95.
  63. ↑ 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.
  64. ↑ Hatters, DM et al. 2005. Modulation of apolipoprotein E structure by domain interaction: differences in lipid-bound and lipid-free forms. J Biol Chem 280(4):34288-95.
  65. ↑ 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 lipoproteins. J. Biol. Chem.271:19053–19057.
  66. ↑ 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.
  67. ↑ Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.
  68. ↑ Reynolds, Dawn. Apolipoprotein E. www.chem.cuteu.edu/chem4400/sjbr/dan971.htm.
  69. ↑ Reynolds, Dawn. Apolipoprotein E. www.chem.cuteu.edu/chem4400/sjbr/dan971.htm.
  70. ↑ 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.
  71. ↑ Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.
  72. ↑ Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.
  73. ↑ Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.
  74. ↑ Reynolds, Dawn. Apolipoprotein E. www.chem.cuteu.edu/chem4400/sjbr/dan971.htm.
  75. ↑ 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.
  76. ↑ Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.
  77. ↑ Reynolds, Dawn. Apolipoprotein E. www.chem.cuteu.edu/chem4400/sjbr/dan971.htm.
  78. ↑ 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.
  79. ↑ 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.
  80. ↑ Reynolds, Dawn. Apolipoprotein E. www.chem.cuteu.edu/chem4400/sjbr/dan971.htm.
  81. ↑ 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.
  82. ↑ Reynolds, Dawn. Apolipoprotein E. www.chem.cuteu.edu/chem4400/sjbr/dan971.htm.
  83. ↑ 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.
  84. ↑ 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.
  85. ↑ OMIM.Omim.org/entry/107741.
  86. ↑ Lou, Jinghui et al. 2010. In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network. PLOS.
  87. ↑ 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.
  88. ↑ 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.
  89. ↑ Castellano, Joseph et al. 2011. Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance. Sci Transl Med 3(89).
  90. ↑ 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.
  91. ↑ 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.
  92. ↑ 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.
  93. ↑ 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.
  94. ↑ 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.
  95. ↑ 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.
  96. ↑ 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.
  97. ↑ 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.
  98. ↑ Lou, Jinghui et al. 2010. In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network. PLOS.
  99. ↑ Rall, Stanley C. et al. 1981. Human apolipoprotein e the complete amino acid sequence. The Journal of Biological Chemistry 257(8):4171-4178.
  100. ↑ OMIM.Omim.org/entry/107741.
  101. ↑ 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.
  102. ↑ OMIM.Omim.org/entry/107741.

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