Sandbox Reserved 595: Difference between revisions

=Background=

Apolipoprotein E is a member of the apolipoprotein family (NMR structure [[217b]]).  This soluble protein is produced primarily in the liver and brain; and it is located principally in the plasma and in the central nervous system (CNS)'<ref>Han X.  2010.  T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease.  Mol Neurobiol 41(2-3): 97-106.</ref>'.  The systemic transport of cholesterol and other lipids is this protein's main role in the body '<ref>OMIM.Omim.org/entry/107741.</ref>'.  One minor function it may exhibit is that of immune regulation '<ref>OMIM.Omim.org/entry/107741.</ref>'.  ApoE may also play a role in synaptic integrity and plasticity '<ref>Arold, S. et al.  2012.  Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex.  Acta Neuropathol 123(1):39-52.</ref>'. Particular isoforms, ε2 and ε4 are implicated in hyperlipoproteinemia (HLP III) and late onset Alzheimer's disease (LOAD).   

=Genetics=

The ApoE gene stores the information responsible for the protein apolipoprotein E.  ApoE's cytogenic location is on the long q arm of chromosome 19, in the 13.2 position (19q13.2).  It stretches from base pair 45,409,038 to bp 45,412,649 '<ref>Genetics Home Reference. 2013. APOE gene. Ghr.hlm.nih.gov/gene/APOE.</ref>'.  Polymorphisms for this gene include three main alleles, epsilon 2, epsilon 3, and epsilon 4 '<ref>OMIM.Omim.org/entry/107741.</ref>'.  The ε3 allele is the most frequent in all human groups.  ε4 has a higher frequency in populations such as Pygmies and Khoisan, Aboriginies of Malaysia and Australia, Papuas, some Native Americans, and Lapps.  The frequency of ε2 fluctuates without an apparent trend; but, it is abscent in Native American populations '<ref>OMIM.Omim.org/entry/107741.</ref>'.   

=Structure=

<Structure load='1NFN' size='500' frame='true' align='right' caption='3-D Rendering of ApoE3 N-terminus' scene='Insert optional scene name here' />

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 '<ref>Garai, K and Frieden C.  2010.  The association−dissociation behavior of the ApoE proteins:  

kinetic and equilibrium studies.  Biochemistry 49(44):9533-41.</ref>'.

=Isoforms=

lipoproteins. J. Biol. Chem.271:19053–19057.</ref>'.  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>' '<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  

lipoproteins. J. Biol. Chem.271:19053–19057.</ref>'.  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=

==Immunological==

ApoE can bind lipid antigens.  Once binding occurs, apoE delivers the antigens, via receptor-mediated uptake, into endosomal compartments containing CD1 in antigen-processing cells.  This protein can be secreted by antigen-presenting cells for the purpose of surveying the local environment and transfer microbial lipids from infected cells to bystander antigen-presenting cells.  In one study, apoE mediated the presentation of serum-bovine lipid antigens.  In this way, the immune system has co-opted a component of lipid metabolism in order to raise immunologic responses to lipid antigens '<ref>OMIM.Omim.org/entry/107741.</ref>'.   

=Clinical Relevance=  

==Type III Hyperlipoproteinemia==   

Familial Type III hyperlipoproteinemia is a genetic lipid disorder that is marked by an increase in the concentrations of plasma cholesterol and triglyceride levels '<ref>Rall, Stanley C. et al.  1981.  Human apolipoprotein e the complete amino acid sequence.  The Journal of Biological Chemistry 257(8):4171-4178.</ref>'.  Normally, in individuals whose apoE is functional, chylomicron remnants and VLDL remnants are rapidly removed from circulation via receptor-mediated endocytosis within the liver.  However, this condition develops as a result of apoE that has impaired clearance abilities.  When a defect in apoE of this nature is present, delayed clearance in the plasma of triglyceride-rich lipoprotein remants results; significantly elevated levels of cholesterol-encriched remnant lipoproteins are a defining feature of this disorder '<ref>OMIM.Omim.org/entry/107741.</ref>' '<ref>Kashyap, VS et al.  1995.  Apolipoprotein E Deficiency in Mice: Gene Replacement and