Sandbox Reserved 595: Difference between revisions

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ApoE folds into two independent structural domains that are connected via a hinge region '<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>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>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>'. The amino-terminal domain has a molecular weight of 2kDa and is comprised of the amino acid residues 1-199 (PDB entry [[1nfn]])'<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>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>' '<ref>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.</ref>' '<ref>Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.</ref>'. 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 '<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>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.</ref>' '<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>' '<ref>Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.</ref>'. 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 '<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>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.</ref>' '<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>' '<ref>Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.</ref>'. 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 '<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>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.</ref>'. 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 '<ref>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.</ref>' '<ref>Tamamizu-Kato S et al. 2008. Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E. Biochemistry 4(18):5225-34.</ref>' '<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>' '<ref>Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.</ref>'. 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) '<ref>Tamamizu-Kato S et al. 2008. Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E. Biochemistry 4(18):5225-34.</ref>'. Residues 230-270 in the C-terminal domain are crucial for oligomer formation '<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>'. Those residues that are important for the initiation of lipid binding to ApoE are 261-272 '<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>'.

The carboxyl-terminal domain is 10kD respectively, and consists of the residues 216-299 '<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>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.</ref>'. 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) '<ref>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.</ref>'. 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 '<ref>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.</ref>' '<ref>Tamamizu-Kato S et al. 2008. Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E. Biochemistry 4(18):5225-34.</ref>' '<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>' '<ref>Hatters, DM et al. 2006. Apolipoprotein E structure: insights into function. Trends Biochem Sci 31(8):445-54.</ref>'. 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) '<ref>Tamamizu-Kato S et al. 2008. Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E. Biochemistry 4(18):5225-34.</ref>'. Residues 230-270 in the C-terminal domain are crucial for oligomer formation '<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>'. Those residues that are important for the initiation of lipid binding to ApoE are 261-272 '<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>'.

Connecting the N-terminal and C-terminal domains is the flexible hinge region, which extends approximately from residue 165 to residue 215 '<ref>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.</ref>'(H). This region is protease sensitive '<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>'.

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 (V).

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 '<ref>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.</ref>'.

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 '<ref>OMIM.Omim.org/entry/107741.</ref>'. ''In vivo'', ApoE is almost always associated with lipids and cholesterol. Concentrations of lipid-free ApoE are expected to be insignificant '<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>'.

Sandbox Reserved 595: Difference between revisions

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@@ Line 15: / Line 15: @@
 ApoE folds into two independent structural domains that are connected via a hinge region '<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>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>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>'.  The amino-terminal domain has a molecular weight of 2kDa and is comprised of the amino acid residues 1-199 (PDB entry [[1nfn]])'<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>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>' '<ref>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.</ref>' '<ref>Hatters, DM et al. 2006.  Apolipoprotein E structure: insights into function.  Trends Biochem Sci 31(8):445-54.</ref>'.  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 '<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>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.</ref>' '<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>' '<ref>Hatters, DM et al. 2006.  Apolipoprotein E structure: insights into function.  Trends Biochem Sci 31(8):445-54.</ref>'.  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 '<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>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.</ref>' '<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>' '<ref>Hatters, DM et al. 2006.  Apolipoprotein E structure: insights into function.  Trends Biochem Sci 31(8):445-54.</ref>'.  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 '<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>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.</ref>'.  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 '<ref>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.</ref>' '<ref>Tamamizu-Kato S et al.  2008.  Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E.  Biochemistry 4(18):5225-34.</ref>' '<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>' '<ref>Hatters, DM et al. 2006.  Apolipoprotein E structure: insights into function.  Trends Biochem Sci 31(8):445-54.</ref>'.  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) '<ref>Tamamizu-Kato S et al.  2008.  Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E.  Biochemistry 4(18):5225-34.</ref>'.  Residues 230-270 in the C-terminal domain are crucial for oligomer formation '<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>'.  Those residues that are important for the initiation of lipid binding to ApoE are 261-272 '<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>'.
+The carboxyl-terminal domain is 10kD respectively, and consists of the residues 216-299 '<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>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.</ref>'.  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) '<ref>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.</ref>'.  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 '<ref>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.</ref>' '<ref>Tamamizu-Kato S et al.  2008.  Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E.  Biochemistry 4(18):5225-34.</ref>' '<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>' '<ref>Hatters, DM et al. 2006.  Apolipoprotein E structure: insights into function.  Trends Biochem Sci 31(8):445-54.</ref>'.  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) '<ref>Tamamizu-Kato S et al.  2008.  Interaction with amyloid beta peptide comprises the lipid binding function of apolipoprotein E.  Biochemistry 4(18):5225-34.</ref>'.  Residues 230-270 in the C-terminal domain are crucial for oligomer formation '<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>'.  Those residues that are important for the initiation of lipid binding to ApoE are 261-272 '<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>'.
 Connecting the N-terminal and C-terminal domains is the flexible hinge region, which extends approximately from residue 165 to residue 215 '<ref>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.</ref>'(H).  This region is protease sensitive '<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>'.
-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 (V).
+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 '<ref>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.</ref>'.
 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 '<ref>OMIM.Omim.org/entry/107741.</ref>'.  ''In vivo'', ApoE is almost always associated with lipids and cholesterol.  Concentrations of lipid-free ApoE are expected to be insignificant '<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>'.