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apolipoprotein E (APOE)

Function: - Apo E plays a significant role in chylomicron remnant & intermediate density lipoprotein (IDL) recognition & removal via LRP & the VLDL receptor, respectively - Apo E also plays role in redistribution of cholesterol in membrane biosynthesis - in all tissues, apo E is thought to function in the context of lipoprotein particles [7] Structure: - glycoprotein with at least 4 polymorphic forms: apo E1, apo E2, apo E3, & apo E4 - isoforms differ from one another by a single charge - the forms differ in number of Cys - the substitute amino acid in most cases appears to be arginine. - Apo E2 has 2 Cys, apo E3 1 Cys & apo E4 none Expression: - Apo E is synthesized in the liver & enters the plasma as part of nascent HDL - under the influence of lecithin cholesterol acyltransferase (LCAT), HDL accumulates cholesterol & apo E is transferred to VLDL & chylomicrons - in contrast to most other apolipoproteins, apo E is also synthesized in cells outside of the enterohepatic system, including macrophages, adipocytes & astrocytes. [5, 6]; neurites are mentioned [1] Pathology: - within the brain, apo E binds to the A4 amyloid peptide - it is found within senile plaques - ApoE signalling is also directly linked to dephosphorylation of tau & may protect against formation of paired helical filaments (PHF) & neurofibrillary tangles [8] - polymorphism or defect in APOE are a cause of hyperlipoproteinemia type 3, most frequently apoE2/apoE2 - polymorphism in APOE, apoE4 allele, associated with Alzheimer disease type-2 - cortical thickness of the left entorhinal cortex is children is highest with apoE2 & lowest with apoE4 [18] - defects in APOE are a cause of sea-blue histiocytosis - defects in APOE are a cause of lipoprotein glomerulopathy Genetics: - the 3 major forms are the result of 3 independent alleles acting at a single gene locus; apoE2, apoE3, apoE4 - SNPs in apoE may be associated with human longevity [16,17] Laboratory: - serum protein electrophorsis - E1, apo E2, apo E3, & apo E4 differ from one another by a single charge & accordingly are separated on gels at their isoelectric points of: 5.3 (apoE 1), 5.5 (apo E2), 5.6 (apo E3) & 5.75 (apo E4) Notes: - 1st isolated from plasma in 1972 & was originally known as arginine-rich apolipoprotein

Interactions

molecular events

Related

apolipoprotein E genotype apolipoprotein-E gene CD91, low density lipoprotein (LDL) receptor related protein (LRP) 1, apolipoprotein E [apoE] receptor 1, chylomicron remnant receptor or alpha-2 macroglobulin receptor very low-density lipoprotein receptor; VLDL receptor; VLDL-R (VLDLR)

Specific

apo e1 apo e2 apo e3 apo e4

General

apolipoprotein glycoprotein phosphoprotein

Properties

SIZE: entity length = 317 aa MW = 36 kD COMPARTMENT: extracellular compartment MOTIF: signal sequence {1-18} consensus repeat {80-101} consensus repeat {102-123} consensus repeat {124-145} consensus repeat {146-167} Ser phosphorylation site {S147} LDL receptor binding {158-168} MOTIF: binding site SITE: 162-165 FOR-BINDING-OF: heparin consensus repeat {168-189} consensus repeat {190-211} consensus repeat {212-233} Thr glycosylation site {T212} binding site SITE: 229-236 FOR-BINDING-OF: heparin consensus repeat {234-255} Thr glycosylation site {T307} Ser glycosylation site {S308} SECRETED-BY: hepatocyte astrocyte WITHIN: central nervous system MISC-INFO: CONCENTRATION 2-6 MG/DL

Database Correlations

OMIM correlations MORBIDMAP 107741 UniProt P02649 Pfam PF01442 Entrez Gene 348 Kegg hsa:348

References

  1. OMIM :accession 107741
  2. Clinical Laboratory Medicine, Tilton et al (eds), Mosby Year Book, St. Louis, 1992, pg 129
  3. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. PMID: 8446617
  4. Tietz Textbook of Clinical Chemistry, 2nd ed. Burtis CA & Ashwood ER (eds), WB Saunders Co, Philadelphia PA, 1993, pg 1023
  5. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):507-12. Epub 2001 Jan 9. PMID: 11149950
  6. Pitas et al, Biochim Biophys Acta 917:148, 1987
  7. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  8. Rampon C, Jiang CH, Dong H, Tang YP, Lockhart DJ, Schultz PG, Tsien JZ, Hu Y. Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12880-4. PMID: 11070096
  9. Entrez Gene :accession 348
  10. UniProt :accession P02649
  11. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/APOE
  12. SHMPD; Singapore human mutation and polymorphism database http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=APOE
  13. Wikipedia; Note: apolipoprotein E entry http://en.wikipedia.org/wiki/apolipoprotein_E
  14. Protein Spotlight; Note: Tangled - Issue 83 of June 2007 http://web.expasy.org/spotlight/back_issues/sptlt083.shtm
  15. Strittmatter WJ et al Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81 PMID: 8446617
  16. Sebastiani P et al Genetic signatures of exceptional longevity in humans. PLoS One. 2012;7(1):e29848. Epub 2012 Jan 18. PMID: 22279548
  17. Soerensen M et al Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. PMID: 22234866
  18. Shaw P, Lerch JP, Pruessner JC et al Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PMID: 17509484

Component-of

chylomicron