Sandbox Reserved 595: Difference between revisions

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>'(J). 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>' (J,L). 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>' (J,L). 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>'(I,J,P). 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) (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>'(I,J). 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 (B,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>'.

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 (P). 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 (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).

=Isoforms=

Sandbox Reserved 595: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ 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>'(J).  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>' (J,L).  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>' (J,L).  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>'(I,J,P).  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) (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>'(I,J).  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 (B,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>'.
@@ 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 (P).  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 (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).
 =Isoforms=