Sandbox Reserved 595: Difference between revisions

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==Quarternary 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 (N). Oligomerization also correlates with the length of the C-terminal domain '<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>'. Resulting from this protein's propensity to aggregate is difficulty in determining the full-length three-dimensional structure '<ref>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.</ref>'. 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 (Q).

ApoE proteins self-associate in order to form dimers, tetrameters, and higher aggregates. These phenomena occur in a concentration, pH, and temperature-dependent manner '<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>'. Oligomerization also correlates with the length of the C-terminal domain '<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>'. Resulting from this protein's propensity to aggregate is difficulty in determining the full-length three-dimensional structure '<ref>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.</ref>'. 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 (Q).

=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 '<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>'. 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 '<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 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 '<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 (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 '<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>'. 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 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 '<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>'(H,L). Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 '<ref>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.</ref>'. Accessibility of the hydrophobic residues was higher in apoE4 than apoE3 '<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>'. ApoE4 also has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate '<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>'. 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 '<ref>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.</ref>'. 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 '<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>' '<ref>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.</ref>'(H). Arg112 in apoE4 forms a salt-bridge with Glu109, a feature that apoE3 lacks '<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>'.

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>'(H). Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 '<ref>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.</ref>'. Accessibility of the hydrophobic residues was higher in apoE4 than apoE3 '<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>'. ApoE4 also has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate '<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>'. 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 '<ref>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.</ref>'. 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 '<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>' '<ref>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.</ref>'(H). Arg112 in apoE4 forms a salt-bridge with Glu109, a feature that apoE3 lacks '<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>'.

=Function=

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@@ Line 25: / Line 25: @@
 ==Quarternary 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 (N).  Oligomerization also correlates with the length of the C-terminal domain '<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>'.  Resulting from this protein's propensity to aggregate is difficulty in determining the full-length three-dimensional structure '<ref>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.</ref>'.  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 (Q).
+ApoE proteins self-associate in order to form dimers, tetrameters, and higher aggregates.  These phenomena occur in a concentration, pH, and temperature-dependent manner '<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>'.  Oligomerization also correlates with the length of the C-terminal domain '<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>'.  Resulting from this protein's propensity to aggregate is difficulty in determining the full-length three-dimensional structure '<ref>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.</ref>'.  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 (Q).
 =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 '<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>'.  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 '<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 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 '<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 (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 '<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>'.  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 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 '<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>'(H,L).  Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 '<ref>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.</ref>'.  Accessibility of the hydrophobic residues was higher in apoE4 than apoE3 '<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>'. ApoE4 also has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate '<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>'. 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 '<ref>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.</ref>'.  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 '<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>' '<ref>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.</ref>'(H).  Arg112 in apoE4 forms a salt-bridge with Glu109, a feature that apoE3 lacks '<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>'.
+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>'(H).  Structural stibility of the isoforms, from most stable to least stable, is as follows, E2>E3>E4 '<ref>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.</ref>'.  Accessibility of the hydrophobic residues was higher in apoE4 than apoE3 '<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>'. ApoE4 also has a higher percentage of randomly coiled structure, a feature that could contribute to its greater tendency to aggregate '<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>'. 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 '<ref>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.</ref>'.  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 '<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>' '<ref>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.</ref>'(H).  Arg112 in apoE4 forms a salt-bridge with Glu109, a feature that apoE3 lacks '<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>'.
 =Function=