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 <scene name='Sandbox_Reserved_595/Residue_112/2'>residue 112</scene> in apoE3 and arginine is present at <scene name='Sandbox_Reserved_595/Residue_158/1'>residue 158</scene> (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>'.

[[Image:Apoetable.png|thumb|right|350px]]

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>'.

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 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 '<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>' '<ref>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

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 <scene name='Sandbox_Reserved_595/Residue_112/2'>residue 112</scene> in apoE3 and arginine is present at <scene name='Sandbox_Reserved_595/Residue_158/1'>residue 158</scene> (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>'.
 [[Image:Apoetable.png|thumb|right|350px]]
-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>'.
+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 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 '<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>' '<ref>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