Sandbox Reserved 595: Difference between revisions

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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).

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 ~~(L)~~. 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 (E). 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>' (E,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,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>'.

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 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).
-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 (L).  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 (E).  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>' (E,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,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>'.
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